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  Untreated acute leukemia is rapidly fatal, but a percentage of patients can be cured. In the absence of cure, many can achieve a significant duration of high-quality life depending on preleukemia comorbidities, and should therefore be considered for therapy.

  
  
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  Medical complications of the acute leukemias are often reversed with treatment of the underlying disease.

  
  
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  Bleeding or infectious complications account for the majority of deaths in patients with acute leukemias.

  
  
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  Laboratory findings define and are prominent in tumor lysis syndrome and include hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia.

  
  
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  Rasburicase can be used to treat hyperuricemia, but must be avoided for patients with known hypersensitivity, methemoglobinemia, or G6PD deficiency.

  
  
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  Urinary alkalinization is not recommended for prevention of tumor lysis syndrome.

  
  
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  Cytogenetics and molecular studies are important prognostic indicators in AML and ALL.

  
  
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  Prophylactic platelet transfusion is indicated for thrombocytopenia associated with acute leukemia.

  
  
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  Disseminated intravascular coagulation (DIC) should be aggressively treated with transfusion support with fresh frozen plasma and cryoprecipitate during the initial treatment of acute leukemias.

  
  
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  Acute promyelocytic leukemia (APL) should be suspected in patients with pancytopenia and severe DIC.

  
  
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  All-trans retinoic acid (ATRA) therapy should be rapidly initiated if APL is suspected, and invasive procedures including placement of a central venous catheter should be avoided until the DIC has resolved.

  
  
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  Rapid cytoreduction by hydroxyurea and leukapheresis are mainstays of therapy for hyperleukocytosis.

Acute leukemias are a collection of bone marrow and lymphoid disorders that result from establishment of a malignant stem cell population. Presentation of a patient to medical care with a suspected acute leukemia should be considered a medical emergency, and rapidly involve a specialist in hematologic malignancies and referral to a tertiary care facility with expertise in treatment of patients with acute leukemia. Left untreated, acute leukemias are rapidly fatal within days to weeks of presentation, but with appropriate supportive measures and therapeutic interventions a significant number of patients are cured. For those in whom a cure cannot be achieved, there is still the potential for a substantial period of good quality life. Because of the acuity of these diseases and consequences of their treatment, it is not infrequent that patients with acute leukemias are seen in the setting of a medical ICU.⁴⁵ It is especially important to understand that acute leukemias develop rapidly and the disease itself profoundly compromises an individual’s performance status and comorbidities; however, with rapid and appropriate therapy, these leukemia-induced complications are often reversed. In order to appropriately target care from the perspective of the intensivist, it is important to understand the disease pathophysiology, overall prognostic evaluation, and complications unique to leukemia treatment regimens.

The goal of this chapter is to alert the intensivist to specific issues unique to the management of patients with acute leukemias that can directly impact the course of therapy in a medical ICU setting. We will focus on the diagnosis of leukemia and complications of patients with newly diagnosed or relapsed acute leukemia including cytopenias, tumor lysis syndrome, hyperleukocytosis, disseminated intravascular coagulation (DIC), and infections. Specific classification and prognostic scoring for acute lymphoblastic and myeloid leukemias with special attention to acute promyelocytic leukemia will be discussed as well as the general organization and composition of the current standard treatment protocols for each subtype of leukemia. Several biological and chemotherapeutic drugs are infrequently used outside the treatment of acute leukemias and therapy-associated side effects could directly affect a patient’s acute management in an ICU setting. These will be specifically highlighted at the end of this chapter.

Patients with acute leukemia typically present with a prodrome related to progressive profound cytopenias (ie, neutropenia, anemia, and thrombocytopenia), progressive fatigue, decreased exercise tolerance, petechiae and bleeding, and serious infections including pneumonia. Acute leukemias can profoundly affect coagulation, causing significant DIC, venous thromboembolism and bleeding.

Initial evaluation of a patient with suspected acute leukemia should include a complete blood count with direct evaluation of the peripheral smear for myeloblasts and lymphoblasts as well as for promyelocytes. Although there is often a profound leukocytosis consisting primarily of immature myeloid or lymphoid cells, it is not uncommon for the presenting blood work to show pancytopenia, including leukopenia, with minimal blasts in the peripheral blood smear. In these instances, careful examination of the cells present will often reveal dysplastic features in one or more cell lines.

In addition to a complete metabolic panel, lactate dehydrogenase (LDH) and uric acid levels, careful attention should be paid to coagulation measurements, including prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer and fibrinogen levels. Presence of promyelocytes and severe derangements in coagulation parameters should alert the hematologist and critical care specialist to the potential diagnosis of acute promyelocytic leukemia (APL) and appropriate measures, including rapid initiation of all-trans retinoic acid (ATRA) therapy and correction of coagulopathy, should occur (Table 92-1).

Initial examination should specifically be directed toward signs of infection (cellulitis, pneumonia, or sinusitis), bleeding or thrombosis, and the presence of splenomegaly or hepatomegaly. Additional care should be paid to any symptom that is out of context for the patient’s prior health status (ie, nausea could connote CNS bleed, leukostasis, or leukemic infiltration of the gastrointestinal tract).

When diagnosing the specific form of acute leukemia, the differential diagnosis includes acute myelocytic leukemia (AML), myelodysplastic syndrome (MDS), lymphoblastic leukemia (ALL), and blast-phase chronic myelocytic leukemia (CML). Myelofibrosis (MF) can also present with cytopenias and elevated peripheral myeloblasts. In addition to the above blood work, direct examination of the bone marrow is required for diagnosis and classification of acute leukemia. Both aspirate and trephine biopsy should be obtained from the bone marrow and samples sent for morphology, cytogenetic analysis, flow cytometry, and specific molecular tests as detailed below.

Patients with acute leukemia are immunocompromised at presentation resulting from impaired normal white cell maturation. Most chemotherapy regimens directed at these malignancies induce further myelosuppression often lasting several weeks to a month at a time, and frequently cause mucosal surface injury (ie, mucositis) which creates additional sites for translocation of endogenous organisms into the bloodstream. Clinical practice guidelines for antimicrobial use in neutropenic (ANC <500 cells/mm³) patients with cancer from the Infectious Disease Society of America were recently updated.²⁰ Patients with acute leukemias are at increased risk for gram-negative enteric bacteria, gram-positive cocci and fungi, especially Candida and Aspergillus species. Patients with ALL have abnormal lymphocyte populations, are exposed to prolonged treatment with corticosteroids, and are thus at increased risk for Pneumocystis, mycobacterial, and viral infections. Reactivation of viruses such as cytomegalovirus, herpes zoster, and herpes simplex virus is also common in patients with prolonged leukopenia, and respiratory viruses such as respiratory syncytial virus and influenza are especially virulent and carry a high mortality in this patient population.

Management of infectious complications in patients with acute leukemias is threefold: (1) appropriate prophylaxis against infections, (2) rapid treatment with empiric antibiotics followed by targeted therapy at the onset of fever, and (3) use of granulocyte colony-stimulating factor (G-CSF) as appropriate to the point in therapy for the leukemia. Once the induction chemotherapy is administered, prophylaxis against invasive fungal infections should be started. The standard antifungal prophylaxis has been with fluconazole, which offers good coverage against many Candida species, but lacks activity against invasive mold infections including aspergillosis, zygomycosis, and fusariosis. A seminal article in the New England Journal of Medicine showed a decreased incidence of Aspergillus infection as well as a survival benefit in neutropenic patients with AML who were treated with posaconazole prophylaxis (200 mg three times a day) when compared to fluconazole or itraconazole and is now an approved indication for this drug.¹² Unfortunately, posaconazole is currently available only as an oral suspension that necessitates the ability of the patient to maintain good oral intake for optimal absorption. This is difficult in patients with severe mucositis. Use of proton-pump inhibitors is necessary to decrease the risk of GI irritation from the high-dose corticosteroids used in ALL regimens, but these medications can further hinder posaconazole absorption.^12,33 Evidence for the use of voriconazole prophylaxis in this patient group is not yet definitive, but studies are underway using voriconazole for antifungal prophylaxis in hematopoietic stem cell transplant (SCT) recipients.³³ Antiviral prophylaxis with acyclovir or valacyclovir is started in patients with acute leukemia undergoing induction or reinduction therapy and continued until recovery of the WBC count or resolution of the mucositis, whichever occurs later. Although there is debate about the risk of developing resistant organisms, there is increasing evidence to support the use of fluoroquinolone prophylaxis for high-risk patients with hematologic malignancies with expected durations of prolonged and profound neutropenia (ANC ≤100 cells/mm³ for >7 days).^13,20

Fever in the leukopenic patient (temperature ≥38.3°C) is considered a medical emergency. Rapid collection of blood, urine and sputum cultures, chest x-ray, and initiation of broad gram-negative coverage with agents that cover Pseudomonas aeruginosa are critical. Cefepime or carbapenem monotherapy or semisynthetic penicillin plus an aminoglycoside can be considered for empiric treatment of neutropenic fever. However, a 2010 Cochrane analysis suggested inferior outcomes with cefepime compared to carbapenem monotherapy, although the incidence of Clostridium difficile infection was significantly increased with routine carbapenem use. In considering an aminoglycoside-containing regimen, baseline renal function and nephrotoxicity of concurrent chemotherapy should be taken into account.

For patients who fail to defervesce with appropriately targeted antibacterial agents, detailed radiographic pulmonary evaluation with computerized tomography should be performed. If fungal infection is suspected, empiric antifungal therapy with voriconazole should be started.³³ If the patient is hemodynamically stable, isolation and characterization of the pathogen should be attempted by bronchoscopy with bronchoalveolar lavage and biopsy or by CT-guided needle biopsy. Granulocyte infusion is infrequently used, but G-CSF therapy may be considered depending on the clinical scenario and is best added under the guidance of a hematologic oncologist.

The classification of AML has moved away from the earlier morphologic and cytochemistry based French-American-British (FAB) system. It is now incorporated in the World Health Organization (WHO) system that includes morphology, immunophenotype, cytogenetics, and molecular characterization of the leukemic clone³⁵ and is useful for both classification and prognosis. Risk stratification according to cytogenetics is detailed in Table 92-2. It is worth noting that “normal cytogenetics” is included in the intermediate risk group, but this is dependent on further molecular characterization that modifies prognosis. An increasingly important cytogenetic group is the monosomal karyotype which has an especially poor prognosis (3% overall survival at 4 years with chemotherapy alone) and is defined as two or more autosomal monosomies or one autosomal monosomy and an additional chromosomal structural abnormality.^3,6,35

Well-established molecular studies that assist in risk stratification in AML include FLT3-ITD (internal tandem duplication) (poor prognosis) and NPM1 and CEBPA mutations (favorable prognosis). These are especially helpful in determining prognosis in the “normal karyotype” intermediate risk patient group. Presence of a poor-prognostic molecular marker in a patient with good-risk AML karyotype can alter the decision to rapidly move toward stem cell transplant following induction chemotherapy. There is increasing focus on identification of additional molecular changes that impact prognosis, including c-kit, DNMT3, and FLT3-TKD (tyrosine kinase domain) mutations. However, these are not routinely included in diagnostic studies to date.³

The classification of ALL is based on immunophenotype (ie, pro-B–, pre-B–, mature-B–, pro-T–, common-T–, and mature-T–cell lineage and minimally differentiated ALL or ALL with myeloid markers). As with AML, there are many cytogenetic and molecular abnormalities associated with ALL, the most important of which being the presence of the BCR-ABL transgene [t(9;22)(q34;q11)]. It is especially important to recognize the presence of this transgene as treatment protocols for Philadelphia chromosome positive (Ph⁺) ALL now include a tyrosine kinase inhibitor (imatinib or dasatinib) along with induction therapy.^42,54

Prognostic indicators for adult ALL include age >35 years, WBC >30,000 in B-cell ALL or >100,000 in T-cell ALL, time to complete remission (CR), immunophenotype, karyotype: t(9;22), BCR-ABL, CNS involvement, and persistence of minimal residual disease. As with AML, there are an increasing number of molecular markers that have prognostic significance and continue to be an area of active clinical research. Although the presence of the BCR-ABL transcript (ie, Ph⁺) is still considered a poor-prognostic indicator, the addition of imatinib and dasatinib to standard ALL regimens has significantly improved the prognosis in this patient population to almost that of Ph⁻ ALL patients.^18,42,54

Although originating in the bone marrow, acute leukemias are systemic diseases. Leukemia cells circulate in the bloodstream and are frequently found on biopsy of nonhematopoietic tissues. When AML cells form a solid mass, it is termed a myeloid sarcoma or chloroma. Myeloid sarcomas are most frequently found in bone and subperiostium, lymph nodes, and the gastrointestinal (GI) tract.⁹ Complications of myeloid sarcomas are similar to those encountered with a solid tumor interfering with the normal physiology of the involved organ. Special attention should be paid to these tumors within the spine as they can cause spinal cord compression, and to those within the GI tract as intestinal and biliary obstruction can occur. Granulocytic sarcomas may be treated with local irradiation, but are also responsive to and require treatment with systemic chemotherapy.

Acute leukemias can cause central nervous system (CNS) infiltration with leukemic cells and may be observed as a lymphomatous mass within the brain or spinal cord, or leptomeningeal infiltration with leukemic cells which can be detected by MRI. These are most common with ALL, but can also occur in patients with AML. Age, peripheral WBC count at presentation, detection of blasts in the CSF, and serum LDH are risk factors for CNS leukemia in ALL. Thus, CNS chemoprophylaxis with intrathecal administration of preservative-free methotrexate (12 mg/m² up to a maximum of 15 mg total) and cytarabine (standard and liposomal) are included in all major ALL chemotherapy regimens in a frequency that depends on the likelihood of active CNS disease.³⁰ Intrathecal methotrexate can cause an arachnoiditis, and is therefore coadministered with hydrocortisone (50 mg). CNS chemoprophylaxis has a positive effect on disease-free and overall survival for patients with ALL. Each time that intrathecal chemotherapy is administered, cerebrospinal fluid should be sent for cytology.

If headache and nausea or focal neurologic symptoms are present, dexamethasone (4 mg every 6 hours) can help rapidly alleviate signs and symptoms of CNS edema or swelling. Additional treatment modalities include intrathecal thio-TEPA, whole brain irradiation with 2400 cGy in 12 fractions, local irradiation of spinal lesions, or systemic chemotherapy with high-dose intravenous cytarabine or methotrexate, which can penetrate the blood-brain barrier.

As with the CNS, leukemia cells can infiltrate any solid organ, even without forming a solid tumor as in myeloid sarcomas. Frequently affected organs include the liver, spleen, and kidneys. ALL and blast-phase CML more frequently than AML cause hepatosplenomegaly resulting from leukemic infiltration. Liver infiltration may produce signs of acute hepatitis (jaundice, tender hepatomegaly, and elevated serum transaminases). Liver dysfunction will resolve with systemic chemotherapy, but does limit initial chemotherapy options. Fulminate liver failure can also occur from portal venous thrombus formation and resultant Budd-Chiari syndrome (either as a result of concurrent hypercoagulability or from leukemia cell thrombosis). Thrombectomy or thrombolysis should be considered as appropriate to the patient’s history, as this situation can otherwise be rapidly lethal. Splenic infiltration and enlargement can occur, and increases the risk of infarct, subcapsular hematoma, and rupture. ALL and AML (especially “monoblastic” AML) can also infiltrate the kidneys. Presenting signs include oliguric acute renal failure in the absence of an obstructing lesion. Ultrasound evaluation may show a homogeneous enlargement of both kidneys. Poor renal function can place patients at greater risk of tumor lysis syndrome (ie, hyperkalemia and hyperuricemia and associated complications). If retroperitoneal lymphadenopathy is present, ureteral obstruction can also occur and impair renal function and outflow. This is especially problematic when nephrotoxic chemotherapies are being administered. Appropriate intervention including ureteral stenting should be performed to normalize urinary tract outflow in these instances.