Critical Care of Patients with Hematologic Malignancies

Matthew J. Wieduwilt

Lloyd E. Damon

Introduction

Although the incidence of aggressive hematologic malignancies like acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and intermediate- and high-grade non-Hodgkin lymphomas is low, these potentially curable diseases frequently require intensive care unit (ICU) management at presentation to prevent early mortality and achieve disease remission. Patients with hematologic malignancies account for approximately 2% of all ICU admissions [1,2]. Approximately 7% of patients with hematologic malignancies admitted to the hospital will become critically ill [3]. The most frequently reported indications for ICU admission in patients with hematologic malignancies are respiratory failure (26% to 91%), severe sepsis (8% to 64%), neurologic impairment (14% to 23%), and acute renal failure (14% to 23%). For all critically ill patients with hematologic malignancies, ICU mortality, in hospital mortality and 6-month mortality rates are 23% to 62%, 54% to 82%, and 66% to 83%, respectively [1,2,3,4,5,6,7,8,9,10,11]. Risk factors for death in the ICU include high disease severity score (APACHE II, SAPS II, SOFA), vasopressor use, leukopenia, increasing number of organ failures, and acute renal failure (see Table 115.1). Notably, mechanical ventilation has not been consistently associated with increased risk of death in this patient population, and some studies suggest improved outcomes with early endotracheal intubation [2,12]. In addition, survival in patients with hematologic malignancies admitted to the ICU after chemotherapy alone versus hematopoietic stem cell transplant (HSCT) are not different, suggesting that critically ill HSCT patients should be treated aggressively on ICU admission [13,14]. In fact, when matched for severity of acute illness upon ICU admission, survival of patients with hematologic malignancies and nononcologic patients appears to be similar [1].

Overview of Hematologic Malignancies

Acute Myeloid Leukemia

AML accounts for 22% to 54% of hematologic malignancy admissions to the ICU [1,2,4,6,7,8,9,10,11]. Patients with AML may require ICU admission for disease- or treatment-related complications including sepsis (frequently complicated by neutropenia), bleeding due to thrombocytopenia and occasionally acute disseminated intravascular coagulation and multiple organ failure.

The incidence of AML in the United States is 3.5 cases per 100,000 persons per year with approximately 12,000 new cases diagnosed annually [15]. More than half of newly diagnosed AML patients are over 65 years of age and a third are older than 75 years. Five-year survival rates are approximately 50% in adults under the age of 45 years but drop to less than 10% in patients over the age of 65 [16]. The risk factors for the development of AML, including genetic and environmental factors, have been well defined [17,18,19,20,21,22,23,24,25,26,27].

AML arises from the acquisition of genetic mutations in myeloid precursors or stem cells leading to various degrees of maturation arrest, unregulated proliferation, and resistance to apoptosis. By the World Health Organization 2008 classification system, the diagnosis of AML requires myeloid blasts to comprise 20% or more of nucleated cells in the peripheral blood or bone marrow except in cases of AML with the recurrent cytogenetic abnormalities t(15;17), t(8;21), inv(16)/t(16;16), myeloid sarcoma (a tumor of myeloblasts), and some cases of erythroleukemia [28]. The recurrent cytogenetic abnormalities t(15;17), t(8;21), inv(16)/t(16;16) and normal cytogenetics accompanied by gene mutations in NPM1 or CEBP-alpha confer a better prognosis in terms of risk of relapse, and the majority of patients obtain durable complete remissions with chemotherapy alone [28,29]. Conversely, patients with poor-risk cytogenetics and those with normal cytogenetics accompanied by mutations in the FLT3 proto-oncogene have a low likelihood of durable remission with chemotherapy alone and typically undergo allogeneic HSCT [29].

Standard induction chemotherapy for AML using 3 days of intravenous (IV) anthracycline (daunorubicin, idarubicin) or anthracenedione (mitoxantrone) and 7 days of cytarabine by continuous IV infusion, ideally initiated within 5 days of diagnosis, leads to complete remission rates of 60% to 80% in young adults under 60 years of age and 50% in patients over 60 years of age. Postremission therapy is tailored to pretreatment risk status, performance status and age and may consist of three to four cycles of high-dose cytarabine, autologous HSCT or, for younger patients at high risk of relapse, allogeneic HSCT [30].

Acute Promyelocytic Leukemia

APL accounts for 5% to 6% of all acute myeloid leukemia with approximately 600 to 800 new diagnoses made each year in the Unites States [31,32]. APL frequently presents with acute disseminated intravascular coagulation (DIC) that can be rapidly fatal due to intracerebral, pulmonary, or gastrointestinal hemorrhage, in all accounting for 50% to 60% of early deaths [33]. Early suspicion and treatment of APL, even prior to definitive genetic diagnosis, is important to reduce the risk of life-threatening hemorrhage [34]. Paradoxically, patients are also at risk for thrombotic events that complicate about 10% to 12% of cases, frequently in those with expression of CD2, CD15, and FLT3-ITD mutation [35,36].

APL occurs due to arrest of myeloid differentiation at the promyelocyte stage leading to accumulation of leukemic promyelocytes in the bone marrow, blood, and tissues. Morphologically, leukemic promyelocytes typically have variable
nuclear morphology with bilobed or reniform nuclei, prominent cytoplasmic granules, and numerous large Auer rods, frequently in bundles [37]. Approximately 5% of APL presents as a microgranular variant characterized by few or absent granules [38]. Patients with this microgranular variant tend to have higher presenting white blood cell counts, placing them at higher risk for complications and relapse. Except in rare instances, APL is characterized by the presence of the recurrent cytogenetic abnormality t(15;17)(q22;q12) leading to a PML-RAR-alpha fusion gene that can be demonstrated by cytogenetic analysis, FISH and quantitative RT-PCR [37]. The chimeric PML-RAR-alpha protein is the target of therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), agents that cause degradation of the PML-RAR-alpha oncoprotein thereby promoting terminal differentiation of leukemic promyelocytes [39,40].

Table 115.1 Outcomes of Patients with Hematologic Malignancies Admitted to the ICU

Number of patients	ICU mortality (%)	In-hospital mortality (%)	Risk factors for death	Reference
7,689	43	59	HSCT, Hodgkin lymphoma, severe sepsis, age, length of hospital stay prior to ICU admission, respiratory failure, neurologic failure, renal failure, anemia	[2]
22	55	82	APACHE II score, number of failing organs, mechanical ventilation	[4]
60	—	78	APACHE II score > 30, number of failing organs, resistant disease, leukopenia	[5]
92	—	77	Progression of underlying malignancy	[6]
78	26	—	Number of failing organs, liver failure	[7]
104	44	—	SAPS II score, mechanical ventilation	[8]
124	42	54	Leukopenia, vasopressors, renal failure	[9]
58	62	—	SAPS II score, SOFA score	[10]
24	—	75	SAPS II score > 66, liver failure, neurologic failure, number of failing organs	[3]
92	50	55	SAPS II, SOFA, ODIN, and LODS scores, allogeneic HSCT, neutropenia, severe sepsis, vasopressor use, invasive mechanical ventilation	[11]
101	23	—	SAPS II score, SOFA score, mechanical ventilation, renal replacement therapy	[1]
HSCT, hematopoietic stem cell transplant; SAPS II, Simplified Acute Physiology Score II; APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment; ODIN, Organ Dysfunction and/or Infection Score; LODS, Logistic Organ Dysfunction Score.

The diagnosis of APL should be considered in any patient with a new diagnosis of leukemia especially if accompanied by clinical and laboratory evidence of acute DIC. Early institution of treatment with the differentiating agent ATRA is indicated upon suspicion of APL [32,34]. Careful review of the peripheral blood smear from new leukemia patients in consultation with hematologists and hematopathologists should be performed to look for characteristic hypergranular leukemic promyelocytes. Expedited performance of flow cytometry, specifically evaluating for coexpression of CD34, CD15, and CD13 on the surface of leukemic cells can aide in diagnosing the microgranular variant of APL [41].

Greater than 70% of APL patients attain prolonged remissions with current treatment strategies. Induction chemotherapy regimens generally combine ATRA with an anthracycline, typically idarubicin or daunorubicin [32]. ATO is highly active against APL and in combination with ATRA produces CR rates over 90% [42,43,44]. ATRA or ATO, however, may cause a fatal differentiation syndrome characterized by fever, dyspnea, pulmonary infiltrates, pleuropericardial effusions, weight gain, peripheral edema, renal failure, and hypotension.

Acute Lymphoblastic Leukemia

ALL results from the acquisition of genetic mutations in lymphoid progenitor or stem cells resulting in the arrest of cells at an early stage of differentiation [45]. In 2009, about 5,760 people were diagnosed with ALL in the United States with a median age of 13 years [15]. ALL patients comprise 9% to 27% of ICU admissions for hematologic malignancies [1,2,4,6,7,8,9,10,11]. The 10-year survival among adults with ALL is less than 30% [45,46,47]. Favorable disease characteristics in ALL include ages 1 to 15 years, presenting WBC < 50,000 per μL and rapid achievement of complete remission, whereas age > 35 years is unfavorable. Cases with the t(9;22)/BCR-ABL (Philadelphia chromosome, Ph), representing 15% to 20% of adult cases of ALL, and the t(4;11)/MLL-AF4 translocations typically fare poorly, with survival rates of less than 10% with chemotherapy alone and long term survival after allogeneic HSCT ranging 20% to 45% [48,49,50,51,52,53].

Clinical trial regimens in the last decade have improved complete remission rates to 74% to 93% with 5-year survival rates as high as 48% [54]. Therapy for ALL typically spans 2 to 3 years and includes induction therapy, postremission therapy, central nervous system (CNS) prophylaxis and maintenance chemotherapy in patients who do not undergo HSCT. Induction therapy for ALL typically combines vincristine, an anthracycline (e.g. daunorubicin), and a corticosteroid (prednisone or dexamethasone) with L-asparginase and/or cyclophosphamide. Prophylaxis against CNS relapse includes intrathecal chemotherapy with methotrexate with or without cytarabine and frequently high-dose IV systemic methotrexate. Postremission therapy typically includes the same agents used in induction as well as cytarabine and 6-mercaptopurine. Maintenance therapy consists of oral methotrexate and 6-mercaptopurine often with pulses of vincristine and corticosteroids. Imatinib (Gleevec®) and dasatinib (Sprycel®) inhibit the chimeric BCR-ABL tyrosine kinase produced by the Philadelphia
chromosome and improve complete remission and survival rates in Ph+ ALL [55,56,57,58,59,60,61,62,63]. Ideally, allogeneic HSCT is performed in patients with poor-risk disease.

Aggressive Non-Hodgkin Lymphomas

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma of intermediate grade that typically presents with rapidly enlarging lymph nodes or extranodal masses frequently with symptoms of organ compromise from lymphomatous involvement of extranodal sites. Diagnosis is typically made by excisional biopsy of a lymph node or mass showing large lymphoid cells that completely efface lymph node architecture. Malignant B-cells express CD19, CD20, and CD22 with variable expression of surface immunoglobulin, CD5 and CD10 [64]. Common genetic abnormalities in DLBCL include constitutive expression of the transcriptional repressor Bcl-6, the antiapoptotic protein Bcl-2, and/or the transcription factor c-myc [65]. The International Prognostic Index for aggressive lymphomas uses five unfavorable variables to establish risk status: age greater than 60 years, poor performance status, advanced stage (Ann Arbor Stage III or IV disease), extranodal involvement at more than one site and elevated serum lactate dehydrogenase [66]. First-line combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in combination with the humanized monoclonal anti-CD20 antibody rituximab results in 2-year overall survival rates of 70% to 90% [65].

Burkitt lymphoma (BL), which has the fastest growth rate of any human malignancy, is an aggressive non-Hodgkin lymphoma with endemic, sporadic, and immunodeficiency-associated clinical variants. BL typically presents with rapidly progressive nodal and extranodal disease, commonly in the abdomen and gastrointestinal tract leading to nausea, vomiting, anorexia, bowel obstruction, and gastrointestinal bleeding. Advanced stage is common at diagnosis with bone marrow involvement in 30% to 38% and CNS involvement in 13 to 17% of adults [67]. Morphologically, lymphoma cells are medium-sized with deeply basophilic cytoplasm containing cytoplasmic lipid vacuoles and a high proliferative index of greater than 90%. A leukemic variant exists and can be distinguished from ALL by surface expression of immunoglobulin, CD20 and CD10, without coexpression of TdT or CD34. BL is genetically characterized by chromosomal translocations that lead to constitutive expression of c-myc, typically t(8;14) and rarely t(2;8) or t(8;22)[68]. High-intensity, brief-duration chemotherapy, typically with cyclophosphamide, doxorubicin, vincristine, and antimetabolite-containing regimens, with intensive CNS prophylaxis, have led to 1-year remission rates as high as 86% [67]. The bulky disease and high cell proliferation rates seen in both DLBCL and Burkitt lymphoma place patients at high risk for tumor lysis syndrome and prophylactic treatment with allopurinol to prevent hyperuricemia is typically given prior to chemotherapy.

Other Malignancies

Other notable hematologic malignancies frequently requiring ICU level care are multiple myeloma, Waldenstrom macroglobulinemia and myeloproliferative neoplasms such as chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, and chronic idiopathic myelofibrosis. In multiple myeloma, spinal cord compression may occur due to encroachment of the spinal canal by epidural plasmacytomas and from pathologic fracture of spinal vertebrae. Emergent imaging of the entire spine with MRI is required for diagnosis (see Chapter 116). In Waldenstrom macroglobulinemia, high concentrations of monoclonal IgM paraprotein in the serum can lead to the hyperviscosity syndrome manifest as mucosal bleeding, confusion, seizures, coma, visual disturbance, and/or headache as well as cryoglobulinemia, cold agglutinin hemolytic anemia, and plasma volume expansion leading to congestive heart failure [69]. Myeloproliferative neoplasms may lead to life-threatening hemorrhage or thrombosis, requiring critical care (see Chapter 111).

Disease and Treatment Related Complications

Hyperleukocytosis and Leukostasis

In AML, hyperleukocytosis, generally defined as a circulating blast count greater than 50,000 to 100,000 per μL, occurs in 5% to 18% of patients at initial presentation [70,71]. Early mortality during initial treatment of patients with hyperleukocytic AML ranges from 5% to 30% with advanced age, poor performance status, coagulopathy, respiratory compromise, and organ failure associated with early death [70,71,72,73,74,75]. Hyperleukocytosis in AML is frequently associated with leukostasis manifesting as respiratory failure, visual disturbance, intracranial hemorrhage, and renal failure.

Leukostasis, although typically associated with hyperleukocytosis, can occur at white blood cell counts less than 50,000 per μL (likely due to interpatient variability in leukemia cell biology and individual susceptibility). Myeloid leukemic blasts are less deformable than mature white blood cells possibly predisposing to formation of aggregates of cells in the small blood vessels, tissue ischemia, endothelial damage and tissue infiltration [76,77,78]. In addition, expression of specific cell surface adhesion molecules on leukemia cells and endothelial cell activation by cytokines secreted by leukemic blasts may play important roles in promoting leukostasis. The expression of CD56/NCAM on the surface of leukemia cells in myelomonocytic AML correlates with the development of leukostasis [79]. In vitro, myeloid blasts promote their own adhesion to the vascular endothelium by upregulating expression of ICAM-1, VCAM-1, and E-selectin on endothelial cells [80]. In ALL, hyperleukocytosis is rarely associated with symptomatic leukostasis except with extreme hyperleukocytosis (WBC > 400,000 per μL) possibly due to the smaller size, easier deformability, and decreased vascular endothelium adherence of lymphoblasts [81]. Notably, lymphoblasts in the rare ALL patients with symptomatic leukostasis are less deformable than lymphoblasts from ALL patients without leukostasis [82]. In AML with hyperleukocytosis, most studies have not shown a demonstrable difference in complete response rates, disease free survival or overall survival after treatment [83]. However, the presence of pulmonary leukostasis, hepatomegaly, hyperbilirubinemia, and hypofibrinogenemia are predictors of poor outcome in patients with hyperleukocytosis [74,75,84].

Hydroxyurea at doses of 20 to 30 mg per kg per day or more can reduce peripheral leukocyte counts, and generally requires 1 to 2 days to take effect. Red blood cell transfusions should be avoided until the leukocyte count is less than 50,000 per μL to avoid ischemic events such as stroke or acute coronary syndrome. Although invasive, leukapheresis is a relatively safe procedure and is frequently used in combination with hydroxyurea to rapidly lower circulating blast counts and theoretically decrease the risk of tumor lysis syndrome and progressive leukostasis. Two blood volumes (140 mL per kg) are processed in the typical leukapheresis procedure. Studies have failed to show a consistent clinical benefit with the use of leukapheresis in hyperleukocytic leukemias [85,86,87,88], although some uncontrolled retrospective single institution studies show reduction
of early mortality in patients undergoing leukapheresis without an overall survival benefit [87,88]. Despite the poor prognosis of APL presenting with hyperleukocytosis and organ failure, leukapheresis is contraindicated in this group of patients due to risk of exacerbating acute DIC, initiating vasomotor instability, and increasing induction death [89].

Hyperviscosity Syndrome

The hyperviscosity syndrome occurs in 30% of patients with Waldenstrom macroglobulinemia (also called lymphoplasmacytic lymphoma with IgM monoclonal gammopathy) at presentation and is defined by the presence of increased serum viscosity with neurologic symptoms related to impaired blood flow including headache, vertigo, dizziness, visual impairment, hearing impairment, tinnitus, nystagmus, stupor, stroke, dementia, and coma [90,91,92,93,94,95]. In addition, mucosal bleeding, including GI hemorrhage, renal failure, and congestive heart failure due to plasma volume expansion and concomitant anemia may occur. Elevated serum IgM, with its large pentameric structure, is most commonly associated with hyperviscosity, although the syndrome has been reported with IgA, IgG, and kappa light chain multiple myeloma [96,97,98,99,100,101]. Normal serum viscosity measures 1.4 to 1.8 centipoises [102,103] and symptomatic hyperviscosity typically occurs at greater than 4 centipoises [69].

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