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Management of Acute Myeloid Leukemia in the Intensive Care Setting Andrew J. Cowan, William A. Altemeier, Christine Johnston, Terry Gernsheimer and Pamela S. Becker J Intensive Care Med published online 22 April 2014 DOI: 10.1177/0885066614530959 The online version of this article can be found at: http://jic.sagepub.com/content/early/2014/04/22/0885066614530959

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Article

Management of Acute Myeloid Leukemia in the Intensive Care Setting

Journal of Intensive Care Medicine 1-10 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066614530959 jic.sagepub.com

Andrew J. Cowan, MD1,2,3, William A. Altemeier, MD4, Christine Johnston, MD, MPH5, Terry Gernsheimer, MD1,6, and Pamela S. Becker, MD, PhD1,3

Abstract Patients with acute myeloid leukemia (AML) who are newly diagnosed or relapsed and those who are receiving cytotoxic chemotherapy are predisposed to conditions such as sepsis due to bacterial and fungal infections, coagulopathies, hemorrhage, metabolic abnormalities, and respiratory and renal failure. These conditions are common reasons for patients with AML to be managed in the intensive care unit (ICU). For patients with AML in the ICU, providers need to be aware of common problems and how to manage them. Understanding the pathophysiology of complications and the recent advances in risk stratification as well as newer therapy for AML are relevant to the critical care provider. Keywords intensive care unit, respiratory failure, subdural hemorrhage, tumor lysis syndrome

Introduction Acute myeloid leukemia (AML) is a clonal disorder in which aberrancies in hematopoietic progenitor cells result in the proliferation of immature cells in the blood and bone marrow (‘‘blasts’’). This devastating hematologic disorder commonly results in life-threatening infections and bleeding complications. The most frequent of the myeloid clonal disorders, AML, has an age-adjusted incidence of 3.7 cases per 100 000 per year.1 The specter of disease remains an ongoing concern— in 2013, there are expected to be 14 590 new cases of AML and 10 370 deaths.1 The majority of patients with AML are elders, with a median age of 67 years at the time of diagnosis.1 Despite numerous advances in molecular biology, genomics, and improved risk stratification and prognosis in AML, the standard induction therapy with ‘‘7 þ 3’’—an anthracycline antibiotic, typically daunorubicin, and cytarabine—has remained the same for more than 30 years. For all patients, survival after induction chemotherapy is largely dependent on cytogenetics, age, comorbidities, and performance status. The difference in outcomes between risk categories is notable—patients with unfavorable cytogenetics have a 5-year survival between 11% and 14%, as compared to those with favorable cytogenetics, who have a 5year survival of 55-65%.2,3 Notably, age itself is associated with high-risk cytogenetics and poorer performance status in general, contributing significantly to worse outcomes in this group of patients.4 Patients older than 60 years of age also have more frequent rates of multidrug resistance.4 Allogeneic hematopoietic cell transplantation is now considered for the majority of patients with AML because of its curative potential, excluding those with

good-risk cytogenetics and/or good-risk mutation status, and can now be utilized in patients older than 70 years of age using reduced intensity conditioning. Therapy-related AML (t-AML), defined as AML arising after administration of chemotherapy or chemoradiotherapy, is increasingly common and represents a group of particularly poor-risk AML, representing approximately 10% to 20% of all patients with AML, with the only curative therapy being allogeneic stem cell transplantation.5 Prior exposure to alkylators and/or topoisomerase inhibitors is believed to contribute to the risk. Many of these patients have also had prior exposure to anthracyclines and thus may already have cardiomyopathy or

1

Division of Hematology, University of Washington, Seattle, WA, USA Division of Medical Oncology, University of Washington, Seattle, WA, USA 3 Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA 4 Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA 5 Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA 6 Puget Sound Blood Center, Seattle, WA, USA 2

Received June 12, 2013, and in revised form November 18, 2013. Accepted for publication December 16, 2013. Corresponding Author: Pamela S. Becker, Institute for Stem Cell and Regenerative Medicine, University of Washington Campus Box 358056, 850 Republican St N415, Seattle, WA 98109, USA. Email: [email protected]

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less cardiac reserve before they start induction chemotherapy for t-AML. Complications before, during, or following induction chemotherapy for AML are common. These complications often lead to admission to the intensive care unit (ICU). In the ICU, all hematologic malignancies and in particular acute leukemia have been associated with a poor prognosis.6-8 Common reasons for ICU admissions include respiratory failure, sepsis requiring vasopressors, and neurologic changes.9 Management directed toward specific complications becomes essential in the critical care setting, given the tenuous and fragile substrate of these patients. Important issues, which arise with respect to care in the ICU setting, include prevention and treatment of tumor lysis syndrome (TLS), management of acute kidney injury (AKI), transfusion support, leukostasis and indications for leukapheresis, and ventilator support for acute lung injury (ALI) and alveolar damage. Moreover, infectious complications, including bacterial and fungal infections, are common, given profound cytopenias and result in substantial morbidity and mortality, especially in the elderly patients.10,11 All of these issues may arise either antecedent to or during treatment with cytotoxic chemotherapy. Therefore, it is of relevance to the health care provider practicing primarily in the critical care setting to understand and be familiar with the common complications and management issues that arise in these patients. Moreover, an understanding of the factors influencing outcomes both with respect to mortality following induction chemotherapy and overall mortality, such as performance status and age, is germane to the critical care provider. It is also important to be mindful of the fact that many of these patients can potentially be cured if they can survive a period of critical illness. The goal of this comprehensive review is to provide a guide relevant to patients with AML requiring management in the critical care setting, to illustrate frequent supportive care needs, and to inform the reader of important factors impacting outcomes in this setting.

Hematologic Complications Leukostasis is a challenging clinical condition presenting in 5% to 13% of adults with AML.12 Traditionally, leukostasis has been defined as acute leukemia presenting with a white blood cell (WBC) count in the range of 100 000/mL or greater, with sludging of leukemia cells in vessels leading to compromise of organ function. Leukostasis has long been associated with increased morbidity and mortality and typically incurs damage via impaired vascular circulation leading to tissue hypoxia, most commonly in the lungs and central nervous system (CNS).13 In a broader sense, leukostasis is just 1 manifestation of the syndrome of hyperleukocytosis—which includes TLS and disseminated intravascular coagulopathy (DIC). Clinical manifestations of leukostasis include symptoms of CNS involvement such as confusion, dizziness, headache, tinnitus, and blurred vision and symptoms of pulmonary vascular involvement typically comprise bilateral interstitial or alveolar infiltrates seen on chest film or computed tomography of the thorax. One study evaluated the utility of a scoring system to

stratify patients presenting with leukemia based on severity of pulmonary, neurologic, and other organ system symptoms. This schema was a reliable predictor of leukostasis, albeit only within AML M1 and M2 French-American British (FAB) classification categories.14 A subsequent retrospective review applied this scoring system and confirmed a high score as predictive of early death.15 Treatment of leukostasis has been a controversial area. Both leukapheresis, a procedure in which the WBCs are concentrated and removed from blood while other products are returned to the body, and cytotoxic chemotherapy have been used as treatments of this condition. However, only retrospective studies have examined whether leukapheresis is effective and on the whole, these have only shown an early mortality benefit with no long-term improvement in prognosis.13 To date, no randomized studies have been documented in the literature. Nonetheless, leukapheresis remains the standard of care at some institutions. For the critical care provider, the options available at the treating institution should be taken into consideration, including cytotoxic chemotherapy, keeping in mind that the data supporting the use of leukapheresis are weak and that no outcomes have been definite. Acute promyelocytic leukemia, APL with t(15;17)(q22;q12); PML-RARA by World Health Organization classification or M3 AML by FAB classification, is associated with spontaneous DIC, and regimens including all-trans retinoic acid (ATRA) have reduced but not eliminated DIC. Non-M3 AML is also associated with DIC, which may be provoked by tumor lysis. Disseminated intravascular coagulation is a consumptive coagulopathy; common laboratory abnormalities include thrombocytopenia, elevated fibrin degradation products, prolonged prothrombin time and partial thromboplastin time, and low fibrinogen.16,17 These derangements are more pronounced both during and following treatment with cytotoxic chemotherapy.18 Septic or cardiogenic shock may also contribute to DIC. Treatment is targeted to the underlying condition when possible, such as sepsis. However, to abrogate complications, depending on the predominant DIC manifestation, blood product support is the mainstay of treatment. Historically, heparin was used for prophylaxis in the pre-ATRA era, but retrospective reports have not shown a benefit, and its general use has fallen out of practice.19,20 Typically for patients in active DIC, cryoprecipitate is transfused for fibrinogen levels less than 100 mg/dL, and platelet transfusions for platelet counts 1 pulmonary infiltrate, high respiratory rate, age older than 60 years, and Eastern Cooperative Oncology Group (ECOG) performance status 2. Moreover, approximately two-third of the patients who experienced a respiratory event developed respiratory failure. Taken together, these findings suggest that predictive factors may help to identify patients at risk of pulmonary failure and should alert the intensive care practitioner to those patients requiring closer monitoring. Literature is scarce regarding management specific to patients with AML having acute respiratory failure. Bronchoscopy with bronchoalveolar lavage (BAL) is commonly used in an attempt to identify specific etiologies such as bacterial or viral infections or alveolar hemorrhage. Additionally, a negative bronchoscopy, particularly if performed prior to the onset of antibiotic therapy, may provide indirect supportive evidence of chemotherapy-associated lung injury. However, at least 1 study suggests that bronchoscopy results in a significant change in therapeutic approach only 17% of the time.44 Patients are typically treated with broad-spectrum antibiotics until either a specific etiology of respiratory failure is identified or the patient is clinically improved. Although patients with

hematologic malignancies were specifically excluded from the Acute Respiratory Distress Syndrome (ARDS) Network ARMA trial, lung protective ventilatory strategies should be used in patients with leukemia and hypoxic respiratory failure associated with multifocal infiltrates who require mechanical ventilation.45 Although limitation of intravascular volume overload is associated with increased ventilator-free days in the general ARDS population,46 implementation of aggressive fluid restriction algorithms in the leukemic population must be carefully considered given the increased risk of AKI and associated mortality in these patients. Specifically, intravenous (IV) hydration is indicated during induction chemotherapy to prevent complications of TLS in patients with high leukemic burden.

Infectious Complications Infections, most commonly bacterial or fungal, are common problems encountered in patients with AML, especially during induction chemotherapy and subsequent aplasia. For those younger than the age of 60, a recent report demonstrated a 58% rate of documented infections in patients undergoing induction chemotherapy and a rate of 70% in those older than 60 years of age.39 One-third of patients undergoing consolidation chemotherapy develop infection.47,48 Invasive fungal infections, such as invasive aspergillosis, occur commonly during induction chemotherapy and account for substantial morbidity and mortality.49-54 Febrile episodes are common in patients with AML undergoing induction chemotherapy, and while the source is often identified, the etiologic organism is not discovered in about 50% of cases.55 Patients with AML commonly develop mucositis and have central venous catheters, both of which constitute significant breaches to the immune system in these fragile patients. Indeed, in a retrospective study of patients with AML undergoing cytotoxic chemotherapy with antibiotic prophylaxis, of the 81% of fevers in which a source was identified, the most common were mucositis in 21.7%, pneumonia in 13.2%, central-venous catheter infection in 12.4%, neutropenic enterocolitis in 9.3%, and invasive fungal disease in 9.3%.56 Pulmonary infections are believed to be a common source for neutropenic fevers.57 Given the broad differential diagnosis of fever in the ICU patients with neutropenia, infectious disease physicians should be consulted to assist with diagnosis and management of complex antimicrobial regimens.58 Standard, evidence-based empiric antimicrobials for neutropenic fever are appropriate supportive care for patients with AML, both prior to and during induction chemotherapy. The source of bacterial infections is typically translocation from the gastrointestinal (GI) tract due to chemotherapeutic toxicity as well as neutropenia; bacteremias are often polymicrobial. Therefore, empiric antibiotics should include coverage against gramnegative organisms, including pseudomonas. The most recent Infectious Diseases Society of America (IDSA) guidelines for neutropenic fever recommend monotherapy with an

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antipseudomonal b-lactam agent, a carbapenem, or piperacillin– tazobactam.59 Patients presenting with sepsis may also have aminoglycoside added as empiric coverage until microbiologic data are available.59 Additional antimicrobial therapy should be added based on the clinical situation.59 Clinical decision making should also be guided by institution-specific patterns of resistance among common causative pathogens. Notably, gram-positive infections have been documented in greater frequency than gram-negative infections in recent literature, likely reflecting improved antimicrobial prophylaxis.56 In particular, streptococcal bacteremias due to oral flora may cause fulminant sepsis with ARDS in patients with neutropenia.60 Receipt of high-dose cytarabine, a very common chemotherapy drug used in AML, has been associated with gram-positive coccal infection61 for which mucositis has also been identified as a risk factor.60 Empiric grampositive coverage should be included for critically ill patients presenting with hemodynamic instability or sepsis or for patients with severe mucositis.60 Providers should also be aware of the possibility of resistant organisms, such as methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococcus, or extended-spectrum b-lactamases, or difficult to treat organisms, such as Stenotrophomonas maltophilia, which may be present in these patients. Besides antibiotics, no other specific supportive measures exist to ameliorate outcomes with neutropenic fever. A randomized, multicenter, and phase 3 trial of granulocyte transfusions in patients with neutropenic AML having infections is ongoing to elucidate the benefit of this therapy (ClinicalTrials.gov identifier NCT00627393). A common source of fever in the critically ill patients with AML is neutropenic enterocolitis, also known as typhlitis. This condition is characterized by the clinical presentation of fever and abdominal pain in the setting of profound neutropenia. Ultrasound and computed tomography may show bowel wall thickening, nonspecific colitis, or phlegmon.62 Previously a complication of induction chemotherapy seen predominantly in the pediatric population, the incidence of neutropenic enterocolitis has been rising in adults, with a pooled rate of 5.6% in the adult acute leukemic population undergoing induction chemotherapy. Treatment for this condition is typically conservative, with bowel rest, hydration, and antibiotics as the mainstay, although surgical interventions may be necessary in certain circumstances such as uncontrolled hemorrhage or bowel perforation.63 Patients with AML have multiple risk factors for development of Clostridium difficile-associated diarrhea (CDAD), including hospitalization and exposure to fluoroquinolones.64 Retrospective series have shown that CDAD occurs in *14% to 18% of patients undergoing chemotherapy for AML.65,66 Recent studies have shown that in patients with severe C difficile infection, treatment with oral vancomycin is associated with better cure rates than oral metronidazole.67 The Zar criteria67 and Belmares criteria68 may provide better assessment than the 2010 IDSA/Society for Healthcare Epidemiology of America scoring criteria of the severity of C difficile infection in patients with

hematologic malignancies, because they do not rely on the presence of an elevated WBC.69 Patients with neutropenia having AML are also at high risk of candidemia, which may present with septic shock in 10% of cases.70 Although antifungal prophylaxis is used during neutropenia, breakthrough candidemias account for nearly half of the candidemias in patients with leukemia.70 Patients with hematologic malignancies have nonalbicans candidemia in approximately two-third of the cases, which may be resistant to azole therapy. Therefore, echinocandins are preferred for proven or suspected candidemias in the critically ill patients with recent azole exposure.71 Invasive aspergillosis, a feared complication of prolonged neutropenia in AML following cytotoxic chemotherapy, should be suspected in a patient with AML having recurrent neutropenic fevers and negative bacterial cultures on broad-spectrum antibiotics. This infection has had decreasing rates over the last decade, likely due to improved fungal prophylaxis. Nonetheless, disseminated aspergillus remains a complication associated with high morbidity and mortality nearing 100%. Currently, diagnosis of invasive aspergillus remains an area of controversy, but a recent study showed that initial screening with galactomannan enzyme assay followed by high-resolution computed tomography and bronchoscopy with BAL resulted in earlier initiation of antifungals, which is likely a reasonable diagnostic algorithm.72 The treatment of choice for invasive aspergillus is voriconazole.73 Evidence-based guidelines recommend early initiation of antifungal therapy, even while confirmatory testing is pending. At this time, the current recommended frontline treatment for critically ill patients is IV voriconazole, with liposomal amphotericin B as an alternative in select patients.74 Disseminated fungal infections such as fusarium and aspergillus may present with sepsis and erythematous nodular cutaneous lesions.75 Disseminated fusariosis infection also has extremely high mortality in patients with neutropenia, approaching 80%.76 Critically ill patients with AML should have careful skin examinations daily with low threshold to perform skin biopsy for fungal stains and culture on new lesions. Given the relatively high frequency of invasive fungal infections seen with prolonged neutropenia, prophylaxis of fungal infections has seen an increasing role in patients with AML in recent decades. Initial data were obtained from the allogeneic transplant population, where prophylaxis with fluconazole was shown to prevent mortality attributable to invasive fungal infections.77,78 More recently, trials studying the use of posaconazole, a newer triazole antifungal, have shown better efficacy for prevention of invasive fungal infections in patients with neutropenia undergoing induction chemotherapy than fluconazole or itraconazole with improved overall survival.79 Infection with respiratory viruses can also complicate the course, due to profound lymphopenia, which is associated with increased risk of lower respiratory tract infection.80,81 Patients with respiratory symptoms, including respiratory failure, should have nasal wash or BAL sent for a wide range of respiratory viral pathogens such as influenza, parainfluenza

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respiratory syncytial virus (RSV), human metapneumovirus, and adenovirus,59 preferably by polymerase chain reaction. If influenza is suspected, empiric therapy with the appropriate anti-influenza agent should be initiated. The RSV pneumonia may also require treatment in patients with AML. Although neutropenia is just 1 reason of many that patients with AML are prone to developing fever and sepsis—others include altered gut mucosal integrity, disruption of normal microbial contents of the GI tract—neutropenia is 1 potential factor, which can be mitigated by the use of myeloid growth factors (MGFs).82 Indeed, the use of growth factors is indicated in the treatment of many malignancies where the risk of febrile neutropenia is high.82 However, the use of MGFs in AML is somewhat more controversial. A large randomized trial performed by the Medical Research Council did not show any benefit to use of granulocyte colony-stimulating factor (CSF) as supportive therapy following intensive induction chemotherapy in patients with AML.83 Moreover, a recent metaanalysis and systemic review performed by the Cochrane group did not disclose any improvement in overall survival or infectious complications with the use of MGFs postchemotherapy.84 Taken together, these results suggest that although time to neutrophil recovery may be improved, and in the context of the ICU, this may be of some acute benefit, although overall survival is not impacted.

Acute Kidney Injury in AML Acute kidney injury is a common complication observed in patients with AML, reported in 30% to 46% of patients.85,86 Common causes for AKI in this patient population include septic shock-induced acute tubular necrosis, TLS, dehydration, medication, and leukemic infiltration of the kidneys. Pertaining to the critical care setting, a strong correlation was noted between development of ALI and AKI; this has been hypothesized to be due to systemic cytokine release seen in both conditions.85 Nephrotoxic antibiotics such as amphotericin B and vancomycin were significantly associated with development of AKI.85 Hemodialysis has been used in patients with AML having AKI; however, it is associated with high mortality. In a retrospective study of patients with acute leukemia, dialysis was required in 8% of patients, with a median survival of 33 days and an overall mortality of 60%.85

Metabolic Abnormalities and AML Metabolic and electrolyte imbalances are frequently seen in the patients with AML undergoing induction chemotherapy and to an even greater degree in the ICU. The principal metabolic derangement encountered is TLS. The commonly used Cairo and Bishop laboratory definition of TLS is the presence of hyperuricemia, hyperkalemia, hypophosphatemia, and hypercalcemia.87 Clinical TLS may be defined as biochemical TLS in addition to AKI or oliguria, cardiac arrhythmias, seizures, or death. Tumor lysis syndrome can also be classified as either spontaneous—due to rapid cell turnover prior to administration

of cytotoxic chemotherapy, or related to treatment and rapid cell death.88 Traditionally, spontaneous TLS has been considered less common in AML, but a recent study refuted this, reporting an incidence of 25%.89 Although patients with AML might be admitted to critical care units for other presentations such as sepsis, neutropenic fever, or ALI, clinicians need to be aware of the risk of development of TLS in all patients with AML regardless of whether cytotoxic chemotherapy has commenced. A recent study attempted to create a risk score for TLS, based on 3 variables found to be significant in retrospective multivariate analysis, including serum lactate dehydrogenase, serum uric acid, and gender.90 A score is generated based on the presence of these factors from 1 to 10, with 10 having a 78% probability of TLS, as compared with 1 having a 9.8% probability of TLS. The germane concern for the critical care provider is to predict with some degree of accuracy which patients will develop TLS and to manage these patients appropriately. Scoring systems such as these should enable them to do so. Although critical care providers will more often be treating, rather than preventing TLS, understanding principles and practice of prevention is also important. The mainstay of prevention in at-risk patients includes hyperhydration, reduction in serum uric acid levels with allopurinol, and monitoring of serum potassium and calcium levels.91 Patients with bulky tumors or organ involvement are at elevated risk of development of TLS and should therefore undergo more frequent laboratory monitoring. Rasburicase, a recombinant urate oxidase enzyme, is recommended for these high-risk patients.91 Treatment of established clinical or laboratory TLS is similar to prevention and traditionally comprises aggressive hydration, use of allopurinol or rasburicase, and for severe cases with AKI and oliguria, renal replacement therapy.92 Regarding the administration of IV fluids, a typical approach would be to start at 2500 to 3000 mL/m2 d, in patients at the highest risk.91 Typically, concerns regarding volume overload are less of an issue, and diuretics could be considered to improve urine output if this remains persistently low, to target an output of at least 2 mL/kg/h.91

Neurologic Complications in AML For patients with hematologic malignancies, ICH is among the most common complications after infection. Compared with other hematologic neoplasms, AML has been documented to have a much higher incidence of ICH, reported in 6.3% of patients.93 Moreover, ICH is the second leading cause of mortality among patients with AML. Several disease-related factors contribute to this risk, including thrombocytopenia, coagulation factor abnormalities, sepsis, and hyperleukocytosis. In particular, thrombocytopenia is a well-known risk factor, with high baseline prevalence (between 40% and 65%) in patients with AML.94 The mortality rate from ICH in patients with AML, despite advances in supportive care, remains high, with 30-day mortality rates ranging from 32% to 67%.93,95,96,97

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Supportive care measures are important in management of ICH in the patients with AML, which typically involves transfusing platelets to greater than 50 000/mL, and correction of coagulation factor derangements. Prevention of ICH is also important; currently, evidenced-based guidelines recommend maintaining a platelet count greater than 10 000/mL in patients receiving therapy for AML.98 However, although a threshold of 100 000 initially, then 50 000/mL is often used in the setting of ICH, there are no specific guidelines and a paucity of evidence is available to support this or any other specific transfusion threshold in ICH. Cerebral leukostasis has been mentioned previously. Other CNS complications include leukemic meningitis, intracranial chloroma, and posterior reversible encephalopathy syndrome.99

Impact of Performance Status on the ICU Setting Oncologists typically assess functional status as a surrogate marker for the ability of a patient to undergo treatment with cytotoxic chemotherapy. Commonly used measures include Karnofsky performance status (KPS) and ECOG (Zubrod) performance status.100 For example, the often used ECOG performance status uses a score from 0 to 4, where 0 denotes a fully active person without any functional impairment and 4 is a person who is completely disabled. Functional status and therefore performance status are well accepted by health care providers as declining with age. Indeed, in the AML population, in a retrospective study using Southwestern Oncology Group (SWOG) trials, more elderly study participants with AML often presented with poorer performance status.4 Given the established correlation between performance status and age, clinicians are likely to consider age as a surrogate marker for performance status and treat accordingly. Primarily, this impacts patients being considered for cytotoxic chemotherapy, but undoubtedly, in the critical care setting, a resource-intense area of medicine where increasing pressure is evident to reduce expenditures, age, and performance status likely impact clinician decisions. Recent evidence, however, argues against jumping to this conclusion prematurely. A study of 63 patients with AML presenting to a tertiary care center found that, in a multivariate analysis, the most significant predictors of median survival were instrumental activities of daily living, KPS, and unfavorable cytogenetics. In the multivariate analysis, age was not found to be a significant predictor of median survival.101 The conclusions that can be drawn from this are applicable to the critical care setting, where aggressive life-supporting interventions might be pursued with less vigor in an elderly patient with AML compared to a younger patient, given clinicians, tendencies to associate age with performance status and therefore outcomes. A major issue is what regimens to use to treat AML in patients in the ICU, who may be on ventilators or on dialysis. Most clinical trials have excluded patients with ECOG PS greater than 2 or certainly greater than 3. Therefore, data are lacking on outcomes for patients with AML who are directly admitted to an ICU, who by definition have a performance status of 4.

Conclusion Patients with AML often develop life-threatening complications that necessitate admission to an ICU. These complications arise due to disease-specific complications such as leukostasis, neutropenia, thrombocytopenia, coagulopathy, as well as treatment-related complications such as tumor lysis, lung toxicity, mucositis, intestinal toxicity, and renal failure. Consequences of these include septic shock, life-threatening hemorrhage, and pulmonary and renal failure. Induction chemotherapy typically results in about a 70% complete remission rate for de novo AML. The mortality related to induction chemotherapy has drastically declined over the past few decades, to only 3% to 4%.102 For the majority (about 80%) of patients with AML who will not be cured with conventional chemotherapy, allogeneic hematopoietic cell transplantation provides a potential curative option. Given that supportive care alone has improved median survival for patients with AML since the 1990s, the importance of these life-saving interventions must not be understated in the critical care setting, and the potential for cure of the leukemia should be a critical component of the medical decision making involved in commitment to aggressive care. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. http://seer.cancer.gov/csr/1975_2010/. Based on November 2012 SEER data submission, posted to the SEER web site. June 1, 2013 2. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukaemia working parties. Blood. 1998;92(7):2322-2333. 3. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/ Eastern Cooperative Oncology Group Study. Blood. 2000; 96(13):4075-4083. 4. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481-3485. 5. Klimek VM. Recent advances in the management of therapyrelated myelodysplastic syndromes and acute myeloid leukemia. Curr Opin Hematol. 2013;20(2):137-143. 6. Brunet F, Lanore JJ, Dhainaut JF, et al. Is intensive care justified for patients with haematological malignancies? Intensive Care Med. 1990;16(5):291-297.

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7. Carlon GC. Admitting cancer patients to the intensive care unit. Crit Care Clin. 1988;4(1):183-191. 8. Schuster DP, Marion JM. Precedents for meaningful recovery during treatment in a medical intensive care unit. Outcome in patients with hematologic malignancy. Am J Med. 1983;75(3): 402-408. 9. Benoit DD, Vandewoude KH, Decruyenaere JM, Hoste EA, Colardyn FA. Outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication. Crit Care Med. 2003;31(1):104-112. 10. Bennett CL, Hynes D, Godwin J, Stinson TJ, Golub RM, Appelbaum FR. Economic analysis of granulocyte colony stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial. Cancer Invest. 2001;19(6):603-610. 11. Gurion R, Belnik-Plitman Y, Gafter-Gvili A, et al. Colonystimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. Cochrane Database Syst Rev. 2012;6:CD008238. 12. Porcu P, Cripe LD, Ng EW, et al. Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management. Leuk Lymphoma. 2000;39(1-2):1-18. 13. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis and leukapheresis: practice management. Blood Rev. 2012;26(3):117-122. 14. Novotny JR, Muller-Beissenhirtz H, Herget-Rosenthal S, Kribben A, Duhrsen U. Grading of symptoms in hyperleukocytic leukaemia: a clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome. Eur J Haematol. 2005;74(6):501-510. 15. Piccirillo N, Laurenti L, Chiusolo P, et al. Reliability of leukostasis grading score to identify patients with high-risk hyperleukocytosis. Am J Hematol. 2009;84(6):381-382. 16. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British committee for standards in haematology. Br J Haematol. 2009;145(1):24-33. 17. Marti-Carvajal AJ, Simancas D, Cardona AF. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev. 2011;(6):CD008562. 18. Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost. 2001;27(6):593-604. 19. Goldberg MA, Ginsburg D, Mayer RJ, et al. Is heparin administration necessary during induction chemotherapy for patients with acute promyelocytic leukemia? Blood. 1987;69(1):187-191. 20. Stein E, McMahon B, Kwaan H, Altman JK, Frankfurt O, Tallman MS. The coagulopathy of acute promyelocytic leukaemia revisited. Best Pract Res Clin Haematol. 2009;22(1):153-163. 21. Wada H, Thachil J, Di Nisio M, et al. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines [published online February 4, 2013]. J Thromb Haemost. 2013. 22. Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy:

23.

24.

25.

26.

27.

28.

29. 30.

31.

32.

33.

34.

35.

36.

37.

38.

characteristics, outcome, and prognostic factors. Blood. 2009; 113(4):775-783. Rogers JE, Yang D. Differentiation syndrome in patients with acute promyelocytic leukemia. J Oncol Pharm Pract. 2012; 18(1):109-114. Larson RS, Tallman MS. Retinoic acid syndrome: manifestations, pathogenesis, and treatment. Best Pract Res Clin Haematol. 2003; 16(3):453-461. No authors listed. Leukocyte reduction and ultraviolet b irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization To Platelets Study Group. N Engl J Med. 1997;337(26):1861-1869. Dawson MA, Avery S, McQuilten ZK, et al. Blood transfusion requirements for patients undergoing chemotherapy for acute myeloid leukemia how much is enough? Haematologica. 2007; 92(7):996-997. Stanworth SJ, Estcourt LJ, Powter G, et al. A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med. 2013;368(19):1771-1780. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. N Engl J Med. 1997;337(26):1870-1875. Schiffer CA. Management of patients refractory of platelet transfusion. Leukemia. 2001;15(4):683-685. Sintnicolaas K, van Marwijk Kooij M, van Prooijen HC, et al. Leukocyte depletion of random single-donor platelet transfusions does not prevent secondary human leukocyte antigenalloimmunization and refractoriness: a randomized prospective study. Blood. 1995;85(3):824-828. Kalmadi S, Tiu R, Lowe C, Jin T, Kalaycio M. Epsilon aminocaproic acid reduces transfusion requirements in patients with thrombocytopenic hemorrhage. Cancer. 2006;107(1):136-140. He´bert PC, Wells G, Blajchman MA, et al. A multicenter randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6):409-417. Webert KE, Cook RJ, Couban S, et al. A multicenter pilotrandomized controlled trial of the feasibility of an augmented red blood cell transfusion strategy for patients treated with induction chemotherapy for acute leukemia or stem cell transplantation. Transfusion. 2008;48(1):81-91. Valeri CR, Cassidy G, Pivacek LE, et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion. 2001;41(8):977-983. Ibrahim AS, Spellberg B, Edwards J Jr. Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis. 2008;21(6):620-625. Chaoui D, Legrand O, Roche N, et al. Incidence and prognostic value of respiratory events in acute leukemia. Leukemia. 2004; 18(4):670-675. Rabbat A, Chaoui D, Montani D, et al. Prognosis of patients with acute myeloid leukaemia admitted to intensive care. Br J Haematol. 2005;129(3):350-357. Thakkar SG, Fu AZ, Sweetenham JW, McIver ZA, et al. Survival and predictors of outcome in patients with acute leukemia admitted to the intensive care unit. Cancer. 2008;112(10):2233-2240.

Downloaded from jic.sagepub.com at KANSAS STATE UNIV LIBRARIES on July 18, 2014

Cowan et al

9

39. Atallah E, Cortes J, O’Brien S, et al. Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia. Blood. 2007;110(10):3547-3551. 40. Tremblay LN, Hyland RH, Schouten BD, Hanly PJ. Survival of acute myelogenous leukemia patients requiring intubation/ventilatory support. Clin Invest Med. 1995;18(1):19-24. 41. Rabe C, Mey U, Paashaus M, et al. Outcome of patients with acute myeloid leukemia and pulmonary infiltrates requiring invasive mechanical ventilation-a retrospective analysis. J Crit Care. 2004;19(1):29-35. 42. Andersson BS, Luna MA, Yee C, Hui KK, Keating MJ, McCredie KB. Fatal pulmonary failure complicating high dose cytosine arabinoside therapy in acute leukemia. Cancer. 1990;65(5):1079-1084. 43. Clofarabine, Genzyme Corporation, Cambridge, MA [package insert]; 2013. 44. Rabbat A, Chaoui D, Lefebvre A, et al. Is BAL useful in patients with acute myeloid leukemia admitted in ICU for severe respiratory complications? Leukemia. 2008;22(7):1361-1367. 45. No authors listed. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The acute respiratory distress syndrome network. N Engl J Med. 2000;342(18):1301-1308. 46. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Wiedemann HP, Wheeler AP, et al. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. 47. Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 1996;87(5):1710-1717. 48. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331(14): 896-903. 49. hamilos G, Luna M, Lewis RE, et al. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003). Haematologica. 2006;91(7):986-989. 50. Cornet M, Fleury L, Maslo C, Bernard JF, Brucker G. Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. J Hosp Infect. 2002;51(4):288-296. 51. Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998;26(4): 781-803. 52. Mattiuzzi GN, Estey E, Raad I, et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer. 2003;97(2):450-456. 53. Muhlemann K, Wenger C, Zenhausern R, Tauber MG. Risk factors for invasive aspergillosis in neutropenic patients with hematologic malignancies. Leukemia. 2005;19(4):545-550. 54. Pagano L, Caira M, Picardi M, et al. Invasive aspergillosis in patients with acute leukemia: update on morbidity and mortality—SEIFEM-C report. Clin Infect Dis. 2007;44(11):1524-1525. 55. Cannas G, Pautas C, Raffoux E, et al. Infectious complications in adult acute myeloid leukemia: analysis of the Acute Leukemia

56.

57.

58.

59.

60.

61.

62. 63. 64.

65.

66.

67.

68.

69.

70.

French Association-9802 prospective multicenter clinical trial. Leuk Lymphoma. 2012;53(6):1068-1076. Madani TA. Clinical infections and bloodstream isolates associated with fever in patients undergoing chemotherapy for acute myeloid leukemia. Infection. 2000;28(6):367-373. Gupta A, Singh M, Singh H, et al. Infections in acute myeloid leukemia: an analysis of 382 febrile episodes. Med Oncol. 2010; 27(4):1037-1045. Kerremans JJ, Verbrugh HA, Vos MC. Frequency of microbiologically correct antibiotic therapy increased by infectious disease consultations and microbiological results. J Clin Microbiol. 2012;50(6):2066-2068. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56-e93. Bochud PY, Calandra T, Francioli P. Bacteremia due to viridans streptococci in neutropenic patients: a review. Am J Med. 1994; 97(3):256-264. Cordonnier C, Buzyn A, Leverger G, et al; Club de Re´flexion sur les Infections en Onco-He´matologie. Epidemiology and risk factors for gram-positive coccal infections in neutropenia: toward a more targeted antibiotic strategy. Clin Infect Dis. 2003;36(2): 149-158. Ebert EC, Hagspiel KD. Gastrointestinal manifestations of leukemia. J Gastroenterol Hepatol. 2012;27(3):458-463. Ullery BW, Pieracci FM, Rodney JR, Barie PS. Neutropenic enterocolitis. Surg Infect (Larchmt). 2009;10(3):307-314. Pe´pin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41(9):1254-1260. Gorschlu¨ter M, Glasmacher A, Hahn C, et al. Clostridium difficile infection in patients with neutropenia. Clin Infect Dis. 2001;33(6): 786-791. Schalk E, Bohr UR, Ko¨nig B, Scheinpflug K, Mohren M. Clostridium difficile-associated diarrhoea, a frequent complication in patients with acute myeloid leukaemia. Ann Hematol. 2010;89(1):9-14. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307. Belmares J, Gerding DN, Parada JP, Miskevics S, Weaver F, Johnson S. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect. 2007;55(6):495-501. Wang MS, Evans CT, Rodriguez T, Gerding DN, Johnson S. Clostridium difficile infection and limitations of markers for severity in patients with hematologic malignancy. Infect Control Hosp Epidemiol. 2013;34(2):127-132. Viscoli C, Girmenia C, Marinus A, et al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the invasive fungal infection group (IFIG) of the European organization for research and treatment of cancer (EORTC). Clin Infect Dis. 1999;28(5):1071-1079.

Downloaded from jic.sagepub.com at KANSAS STATE UNIV LIBRARIES on July 18, 2014

10

Journal of Intensive Care Medicine

71. Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007;45(7):883-893. 72. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005;41(9): 1242-1250. 73. Herbrecht R, Denning DW, Patterson TF, et al; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415. 74. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360. 75. Bourgeois GP, Cafardi JA, Sellheyer K, Andea AA. Disseminated Fusarium infection originating from paronychia in a neutropenic patient: a case report and review of the literature. Cutis. 2010; 85(4):191-194. 76. Nucci M, Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer. 2003;98(2):315-319. 77. Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood. 2003;101(9):3365-3372. 78. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326(13):845-851. 79. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356(4):348-359. 80. El Saleeby CM, Somes GW, DeVincenzo JP, Gaur AH. Risk factors for severe respiratory syncytial virus disease in children with cancer: the importance of lymphopenia and young age. Pediatrics. 2008;121(2):235-243. 81. Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Med (Baltimore). 2006;85(5):278-287. 82. Bennett CL, Djulbegovic B, Norris LB, Armitage JO. Colonystimulating factors for febrile neutropenia during cancer therapy. N Engl J Med. 2013;368(12):1131-1139. 83. Wheatley K, Goldstone AH, Littlewood T, Hunter A, Burnett AK. Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom medical research council adult leukaemia working party. Br J Haematol. 2009;146(1):54-63. 84. Gurion R, Belnik-Plitman Y, Gafter-Gvili A, et al. Colonystimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. Cochrane Database Syst Rev. 2012;6:CD008238. 85. Lahoti A, Kantarjian H, Salahudeen AK, et al. Predictors and outcome of acute kidney injury in patients with acute myelogenous

leukemia or high-risk myelodysplastic syndrome. Cancer. 2010; 116(17):4063-4068. 86. Munker R, Hill U, Jehn U, Kolb HJ, Schalhorn A. Renal complications in acute leukemias. Haematologica. 1998;83(5):416-421. 87. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127(1):3-11. 88. Riccio B, Mato A, Olson EM, Berns JS, Luger S. Spontaneous tumor lysis syndrome in acute myeloid leukemia: two cases and a review of the literature. Cancer Biol Ther. 2006;5(12): 1614-1617. 89. Montesinos P, Lorenzo I, Martin G, et al. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica. 2008;93(1):67-74. 90. Mato AR, Riccio BE, Qin L, et al. A predictive model for the detection of tumor lysis syndrome during AML induction therapy. Leuk Lymphoma. 2006;47(5):877-883. 91. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844-1854. 92. 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;26(16):2767-2778. 93. Chen CY, Tai CH, Cheng A, et al. Intracranial hemorrhage in adult patients with hematological malignancies. BMC Med. 2012;10(1):97. 94. Chern JJ, Tsung AJ, Humphries W, Sawaya R, Lang FF. Clinical outcome of leukemia patients with intracranial hemorrhage. Clinical article. J Neurosurg. 2011;115(2):268-272. 95. Chen CY, Tai CH, Tsay W, Chen PY, Tien HF. Prediction of fatal intracranial hemorrhage in patients with acute myeloid leukemia. Ann Oncol. 2009;20(6):1100-1104. 96. Dayyani F, Mougalian SS, Naqvi K, et al. Prediction model for mortality after intracranial hemorrhage in patients with leukemia. Am J Hematol. 2011;86(7):546-549. 97. Kim H, Lee JH, Choi SJ, et al. Risk score model for fatal intracranial hemorrhage in acute leukemia. Leukemia. 2006;20(5): 770-776. 98. Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001; 19(5):1519-1538. 99. Battipaglia G, Avilia S, Morelli E, Caranci F, Perna F, Camera A. Posterior reversible encephalopathy syndrome (PRES) during induction chemotherapy for acute myeloblastic leukemia (AML). Ann Hematol. 2012;91(8):1327-1328. 100. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 101. Wedding U, Rohrig B, Klippstein A, Fricke HJ, Sayer HG, Hoffken K. Impairment in functional status and survival in patients with acute myeloid leukaemia. J Cancer Res Clin Oncol. 2006;132(10):665-671. 102. Othus M, Kantarjian H, Petersdorf S, et al. Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson. Leukemia. 2014;28(2):289-292.

Downloaded from jic.sagepub.com at KANSAS STATE UNIV LIBRARIES on July 18, 2014