A small number of patients are admitted directly to ICUs with life-threatening complications ¹ and require emergency chemotherapy because of specific organ involvement and respiratory, kidney, neurologic, or liver injury. In these cases, chemotherapy must be initiated in the ICU along with the hematologist consultant. From the intensivist’s point of view, emergency chemotherapy may be indicated in seven main clinical situations, independent of the absolute circulating blast counts:

1 Cerebral leukostasis, which should be suspected in the presence of any alteration of consciousness, even a simple slowing down of cognitive functions, once an emergency computed tomography (CT) scan has ruled out an intracranial hemorrhage. Platelet count must be kept as high as possible using large platelet transfusions, disseminated intravascular coagulation (DIC) controlled by urgent chemotherapy, and every effort made to avoid blood transfusion so as to lower viscosity and maintain adequate hydration.

2 Pulmonary leukostasis (generally observed in hyperleukocytotic leukemias) with circulating blast counts greater than 50,000/mm³ for acute myeloid leukemia (AML) or greater than 100,000/mm³ by definition for acute lymphoid leukemia (ALL). However, symptomatic leukostasis is very rare in ALL, even for greatly elevated blasts counts, because of the smaller size and higher plasticity of these blasts.

3 Leukemic infiltration of the lungs, which is different from leukostasis, can occur with low blast counts and is often associated with AML4 or 5. These patients should be admitted to the ICU early in the course of their induction, because rapid deterioration of hematosis is frequent, both spontaneously and after initiation of chemotherapy.²

4 Central nervous system (CNS) involvement suspected on the basis of clinical signs such as focal deficits, seizures, or any degree of alteration of consciousness.³ Here again, intracranial hemorrhage must first be ruled out by a CT scan.

5 Bulky mediastinal involvement with vascular compression (superior vena cava syndrome) or tracheobronchial repercussion, especially as seen in T-cell ALL

6 Threatening DIC with low fibrinogen levels and a prolonged prothrombin time

7 Severe hemophagocytic syndrome with failure of one or more organs. The choice of cytoreductive regimen depends on the type of malignancy, which is not always precisely known on arrival of the patient in the ICU. For acute leukemias, efforts should be made to characterize the lineage (ALL or AML) before treatment is initiated, but if lineage cannot be determined, a non–lineage-specific cytotoxic regimen should be chosen. Intensivists can, therefore, be confronted with five main situations, depending on whether the lineage diagnosis has been established: ALL, AML, promyelocytic leukemia (AML3), acute leukemia of unknown lineage, non-Hodgkin’s lymphoma (NHL), and very rarely, Hodgkin’s disease (HD).

Emergency Chemotherapy in Leukemias

Acute Lymphoblastic Leukemia

Classic induction therapy is based on a 7-day course of steroids alone, followed by a combination of prednisone, vincristine, and an anthracycline (daunorubicin in most studies), with or without the addition of cyclophosphamide.⁴^–⁶ In cases of compressive emergency or high tumor burden, progressive steroid therapy should be prescribed first (beginning with 0.5 mg/kg prednisone for the first dose); patients with high tumor burden should be carefully monitored because they can rapidly develop a severe acute tumor lysis syndrome (ATLS).⁷^–¹⁰

The steroid dose should be increased to 1 mg/kg/d of prednisolone (or equivalent), 8 to 12 hours after the first dose, in the absence of an uncontrolled ATLS. If ATLS is present, half-dose steroids should be used until metabolic control is regained; in severe ATLS, the second steroid dose could even be postponed. In most cases of ALL, steroids alone will be able to halt the rising white blood cell (WBC) count or initiate the reduction of bulky mediastinal tumors. On day 2 or 3, full-dose vincristine (1 mg/m² of body surface, with a maximum dose of 2 mg/d) and daunorubicin (30 to 60 mg/m², or equivalent anthracycline) should be added; combination with other drugs will be decided by a hematologist according to local protocols.

For patients with increasing or stagnating WBC counts or without biological indicators of tumor response for lymphomas (especially increasing lactate dehydrogenase [LDH] levels) after two full doses of steroids, emergency adjunction of vincristine with or without daunorubicin as early as day 2 is required.

Acute Promyelocytic Leukemia

The main complication of acute promyelocytic leukemia (APL) is DIC, with early mortality essentially related to hemorrhages located in the CNS.¹¹ Nevertheless, although leukostasis in APL is almost never a problem because these patients are usually pancytopenic, their leukemia should be considered (and treated) as hyperleukocytic APL as soon as the WBC count is higher than 5000/mm³. “Variant” type AML3 can be misleading, because patients are not always cytopenic, but they can display true hyperleukocytosis, sometimes greater than 100,000 cells/mm³.

Although APL is remarkably sensitive to anthracyclines, emergency treatment of APL with severe coagulation disorder now relies on early administration of all-trans-retinoic acid (ATRA).^12,¹³ There is no indication for progressive dosing of this drug, which should be prescribed immediately at 45 mg/m²/d in two oral doses taken at 12-hour intervals. Initial worsening of the DIC is the rule, and patients should receive abundant transfusion support to ensure a platelet count above 50,000/mm³ and at least 1.5 g/L of fibrinogen at all times. ATRA is available only in sealed, thick-walled, hardly soluble capsules that contain an oil-based solution. No parenteral form is available. Therefore, administration of ATRA is problematic through nasogastric tubes in mechanically ventilated patients; there is currently no other way than piercing the capsule, emptying its content, and carefully resuspending it in oil to allow injection into a gastric tube.

In hyperleukocytic APL, immediate coadministration of ATRA with daunorubicin is required, starting with half the usual dose (20 to 25 mg/m²/d) for at least 4 days, because transient exacerbation of DIC is almost universal.

Acute Myeloid Leukemia Other Than Promyelocytic Leukemia

Urgent induction is derived from the classic reference treatment, a combination of 3 days of an anthracycline (classically daunorubicin, but idarubicin is one of the many possible alternatives) with 7 days of cytarabine.^4,¹⁴ The difference is that the scheme of administration is progressive: daunorubicin should be administered alone and at half the usual dose (20-25 mg/m²/d for a total of 6 days, equivalent to the 3 days of the standard full-dose regimen) before the continuous infusion of cytarabine (200 mg/m²/d for 7 days) is started on day 3 or 4.

Acute Leukemia of Undetermined Lineage

In cases in which the lineage cannot be determined (e.g., no specialized cytologist on duty, poorly differentiated leukemia requiring complementary immunohistochemical study) and the patient requires urgent chemotherapy, then daunorubicin should be chosen because of its activity on all types of blasts (AML or ALL). In contrast, empirical steroid therapy could be efficient in ALL but not in AML. The scheme of administration would again be half doses of daunorubicin (20-25 mg/m²/d), and the priority should be to have blood or marrow smears reviewed as soon as possible by a trained cytologist so as to get at least the lineage determination within 24 hours. Chemotherapy can then be adjusted accordingly.

Specific Precautions for Leukemic Pulmonary Infiltration

Acute respiratory failure revealing a leukemia is rare, but intensivists should be aware that respiratory failure with bilateral consolidation can reveal nonhyperleukocytic monocytic leukemias (AML5).² This condition should be recognized promptly because it appears to be associated with a high risk of rapid respiratory deterioration after initiation of chemotherapy. However, this should not be viewed as a hopeless complication of a rapidly fatal disease. On the contrary, these patients should receive early invasive or noninvasive ventilatory support and immediate chemotherapy, even if they are not hyperleukocytic and their respiratory impairment is still moderate. The induction treatment is based on low-dose daunorubicin alone (20-25 mg/m²/d) for 2 to 3 days, followed by the introduction of cytarabine. Aggressive supportive care should be initiated in case of respiratory deterioration, because in our experience, 50% of these patients can survive these difficult inductions. It should be noted that blood gas analysis is useless in hyperleukocytic leukemia, since activated blast cells consume oxygen, so oxygen tension rapidly decreases in the syringe.

The Role of Leukapheresis

Therapeutic leukapheresis has been reported to be of benefit for patients with AML who have high WBC counts, and it is routinely used in some centers for acute hyperleukocytic leukemia.¹⁵ However, controversial data have been published, and the results suggest that despite a potential reduction in early mortality, there is no overall improvement in long-term survival.¹⁶^–¹⁸ Optimal supportive care based on hyperhydration, hypouricemic drugs, and prompt induction yields similar results, whether preceded or not by a single oral dose of 2 to 4 g of hydroxyurea, without the complications inherent to the leukapheresis procedure. Based on currently available literature and the fact that this technique is not available 24 hours a day or during weekends in most centers, we cannot recommend its use for unstable ICU patients, and chemotherapy-based cytoreduction protocols should be the first choice. In our experience, leukapheresis should be reserved for failure to decrease blast cells in the presence of clinical symptoms of leukostasis.

Emergency Treatment of Non-Hodgkin’s Lymphomas

Emergency initiation of chemotherapy in non-Hodgkin’s lymphomas (NHLs) can be necessary in the following clinical situations ¹:

1 Massive pleural or pulmonary involvement compromising hematosis

2 Bulky mediastinal tumor with compression of trachea or main bronchi

3 Poorly tolerated superior vena cava syndrome

4 CNS localization with alteration of consciousness

5 Spinal cord compression

6 Airway compromise in cases of pharyngeal localization

7 Pericardial or cardiac involvement

8 Occlusive syndrome in massive abdominal tumors

In these cases, initiation of chemotherapy may be required before exhaustive assessment of the disease has been completed, or even before definitive typing of the lymphoma has been established, thus complicating the therapeutic choices.¹⁹ Nevertheless, most of these life-threatening complications occur in the setting of aggressive large-cell lymphomas, and the important point is not to choose the optimal protocol for a specific NHL but to be efficient in ensuring survival with limited toxicity in these patients with compromised respiratory, cardiac, renal, or hepatic functions.

All of these patients should receive adequate preventive treatment for ATLS, and they should be closely monitored for the occurrence of this syndrome during the first 3 days.⁷^–⁹

Burkitt’s Lymphomas

The risk of an overwhelming ATLS is so high in patients with Burkitt’s lymphomas that steroids alone should be administered first and in increasing doses. Most protocols recommend that known or suspected Burkitt’s lymphomas with high tumor burden be treated with a cytoreductive course of chemotherapy before full-dose chemotherapy is administered.²⁰^–²³ The consensual choice is to deliver a first initial dose of 0.25 to 0.5 mg/kg of methylprednisolone, with the following dose administered 8 to 12 hours later if no uncontrolled metabolic disorder related to an ATLS is observed. In “steroid responders,” lysis will be obvious on biological criteria, especially the elevation of LDH, even in the absence of an obvious ATLS. Dosing should then be increased to 1 mg/kg/d on day 2, before infusion of one dose of vincristine and one dose of cyclophosphamide (dosing specified below) on day 2 or 3, depending on the response to steroids. If no sign of lysis occurs after two doses of steroids (as revealed by stable LDH levels), the addition of one dose of vincristine is usually sufficient to initiate a spectacular response. The cyclophosphamide dose is delivered on the following day if the ATLS is controlled. We recommend prophylactic hemodialysis in patients without kidney injury but with hyperphosphatemia before any chemotherapy of steroid therapy. Indeed, if the use of rasburicase has dramatically decreased the risk for uratic nephropathy, nephrocalcinosis remains a potential complication that can be prevented only by lowering blood phosphate levels.

Threatening Non-Burkitt’s, Non-Hodgkin’s Lymphomas

With the exception of confirmed or suspected Burkitt’s lymphomas (which require smaller doses of steroids on day 1), treatment of bulky NHLs should be started with steroids at 1 mg/kg/d of methylprednisolone or equivalent on day 1 and completed as early as day 2 with vincristine (1 mg/m² once, maximum total dose 2 mg, in the absence of severe preexisting peripheral neuropathy) and cyclophosphamide (500-700 mg/m²) on day 2 in the absence of uncontrolled ATLS.²⁰^–²²

Whether bulky or not, NHLs with immediate life-threatening localization can require that all three drugs be infused on day 1, but intensivists should then be aware of the increased risk of uncontrolled ATLS, which may require extrarenal replacement.

Central Nervous System Involvement

Patients with NHL of the CNS who display focal deficits, alterations of the level of consciousness, or seizures should receive emergency steroid therapy with at least 2 mg/kg/d of methylprednisolone or equivalent. Optimal dosing is controversial in the literature, and doses ranging from 2 to 4 mg/kg/d can be considered appropriate. Administration of high-dose methotrexate, a key drug in the treatment of CNS NHL, is not necessary in an emergency situation and requires normal renal and liver functions.^3,²⁴

Emergency Treatment of Hodgkin’s Disease

Emergency chemotherapy is a rare necessity in HD, but life-threatening mediastinal or cardiac involvement is possible, compromising oxygenation or hemodynamic stability. Nevertheless, one should remember that HD is a slow-responding tumor, so no spectacular reduction of tumor burden should be expected within 24 or 48 hours after the initiation of chemotherapy, and decisions regarding supportive care should take into account this parameter.

HD is not a steroid-sensitive disease, no single drug is rapidly efficient, and no recommendation is available in the literature regarding urgent cytoreduction in HD. Therefore, if a decision for emergency chemotherapy is made, a standard combination may be recommended: bleomycin, 10 units/m²; vinblastine, 6 mg/m²; doxorubicin, 25 mg/m²; and dacarbazine, 375 mg/m²—all administered on day 1 in the absence of cardiac or pulmonary contraindications.²⁵^–²⁷

Blastic Meningitis

Although prophylactic intrathecal chemotherapy is required in all patients with ALL or hyperleukocytic AML, very few patients require urgent intrathecal chemotherapy (coma, seizures, cauda equina syndromes).³ Therefore, specialized consultation should always be obtained before administering any intrathecal chemotherapy, even in the presence of highly suggestive symptoms such as peripheral radicular pains or deficits or hyposensitivity or dysesthesia of the chin (infiltration of the dental nerve). In addition, lumbar puncture, even for exploratory purposes, is contraindicated in patients with hyperleukocytosis, to prevent any seeding of the cerebrospinal fluid with blasts during the procedure, and in those patients with marked DIC. Moreover, intensivists should be aware that some cases of ATLS have been described after therapeutic lumbar punctures.

Nevertheless, if the indication of an emergency intrathecal treatment is confirmed, samples of cerebrospinal fluid should always be drawn for biochemical, cytologic, and bacteriologic examination before the chemotherapeutic agents are injected (usually a combination of 15 mg cytarabine, 15 mg methotrexate, and 40 mg conservative free methylprednisolone or equivalent).

Organ Failures Related To Hemophagocytic Syndrome

Severe hemophagocytic syndrome is now well recognized as a common presenting feature in NHL and HD.²⁸^–³⁰ In many cases, organ failures are related to the intensity of the histiocytic activation and not to the invasiveness of the lymphoma itself, which can have a very low tumor burden, making the etiologic diagnosis all the more difficult. The clinical course of these patients is generally fulminant, especially once ICU admission is required.^31,³² The clinical presentation is confounding—it precisely mimics septic shock with fever, chills, vasoplegic shock, acute respiratory distress syndrome, and oliguric renal failure—but severe pancytopenia, high blood transfusion requirements, organomegaly, lymph node enlargement, and hepatic dysfunction several days or weeks before the occurrence of this pseudoseptic shock should suggest the diagnosis of severe hemophagocytic syndrome.³³ Biological features such as elevated serum ferritin and hypertriglyceridemia are precious but inconstant markers of the disease, and the identification of hemophagocytosis on marrow smears or in lymph node or hepatic biopsy samples sometimes requires an experienced cytologist. The 2004 criteria for the diagnosis of hemophagocytic lymphohistiocytosis are listed in Box 154-1.³³

If sufficient clinical and biological elements are highly suggestive of the diagnosis, treatment should be promptly administered to allow emergency control of cytokine-induced organ failures. Treatment of the underlying lymphoma itself can be postponed for 2 or 3 days if the diagnosis is not yet confirmed, until urgent processing and reading of smears or biopsies have been conducted. No randomized trial of chemotherapy has been conducted in lymphoma-related hemophagocytic syndrome, so no consensus is available in the literature regarding the optimal strategy. However, etoposide-based regimens seem to be the most appropriate choice for these high-risk patients,^33,³⁴ frequently in combination with steroids. Based on case reports and our experience, administration of 150 to 200 mg of etoposide, depending on the severity of the renal and hepatic failures, combined with 1 to 2 mg/kg/d of methylprednisolone, is rapidly effective in most cases (within 12-48 hours). The effect is only transient, and recurrence of the initial symptoms is the rule within 6 to 10 days in the absence of a specific treatment of the lymphoma, which should be started by a hematologist as soon as the lymphoma has been identified. If an aggressive NHL is highly suspected on preliminary results of smears (lymph node, marrow, or pleural effusion), a nonspecific cytoreductive combination of steroid, vincristine, and cyclophosphamide can be administered while awaiting the definitive results of the cytologic, histologic, and immunochemistry techniques.

Management of Disseminated Intravascular Coagulation

DIC is a common and serious complication of hematologic malignancies, but most of the time the bleeding is only moderately threatening, with mainly mucosal and cutaneous hemorrhagic manifestations.³⁵ In fact, DIC is often triggered by the initiation of chemotherapy in several types of ALLs and AMLs (AML4, AML5, and to a lesser extent AML1). However, severe forms of coagulation disorders are typically observed as a presenting symptom in untreated acute promyelocytic leukemias (APL or AML3), frequently combining DIC and a severe hyperfibrinolytic state.^13,³⁶ Optimal treatment includes both symptomatic measures to reduce the risk of life-threatening hemorrhage (in the CNS but also in lungs and gastrointestinal tract) and specific treatment of the leukemia.

Supportive care is essential in DIC and should include repeated platelet transfusions to reach a minimum platelet count greater than 50,000/mm³ permanently; correction of the prothrombin time and of hypofibrinogenemia with fresh frozen plasma (2-4 units to start with) to ensure a prothrombin time less than 2.5 times normal; and a fibrinogen level greater than 1 g/L before the start of the treatment.³⁷ The use of low-dose unfractionated heparin (100 International Units/kg/d) is controversial, requires platelet counts permanently superior to 50,000/mm³, and cannot be recommended for patients with active bleeding.^12,^36,^38,³⁹ Its prescription in DIC with thrombotic tendencies should be discussed according to local protocols. As soon as appropriate transfusion support is initiated, chemotherapy should be started, always with progressive dosing, to reduce the leukemic load as quickly as possible. Transient worsening of DIC is common and justifies intensification of transfusions as required by biological and clinical manifestations.

In DIC caused by hematologic malignancies, the use of antithrombin III cannot be recommended based on currently available data, with the exception of severe DICs occurring after infusion of L-asparaginase.⁴⁰^–⁴² In uncontrolled and life-threatening bleeding in nonhematology patients, the adjunctive use of recombinant factor VIIa has yielded some response, but this treatment has never been evaluated in the peculiar case of hematologic malignancies, and further well-designed evaluation of this molecule in severe malignancy-related DIC is needed to recommend its use in hematology patients.⁴³^–⁴⁷

Multiple Myeloma and Other Causes of Hyperviscosity Syndromes

Severe infectious complications and metabolic emergencies (e.g., hypercalcemia, acute renal failure) can lead myeloma patients to the ICU, and these conditions are detailed elsewhere in this text. Myeloma patients can also present with severe organ failures early in the course of their disease. Intensivists should not be discouraged from admitting these patients to the ICU if the disease is not refractory and the patient is in poor condition, because prognosis in the ICU has improved over the years and can justify their admission.⁴⁸ Hyperviscosity syndrome is one specific complication that can initially require ICU admission.

Hyperviscosity syndromes may be encountered in multiple myeloma and Waldenström’s macroglobulinemia, symptomatic forms being more common in the latter.^49,⁵⁰ Clinical manifestations are mainly neurologic (headaches, alteration or slowdown of cognitive function, stupor, even coma, and rarely seizures), ocular (visual impairment, papillary edema with dilated retinal veins, retinal hemorrhages), and excessive bleeding (mainly mucosal, cutaneous, and retinal). Emergency management is directed at rapidly decreasing blood viscosity through plasmapheresis, which leads to rapid alleviation of the initial symptoms. Long-term management, whether based on high-dose steroids or chemotherapy, is aimed at reducing production of monoclonal immunoglobulin and can be postponed until a hematologist consultant has been reached. Plasmapheresis is the only therapeutic option with immediate efficacy^51,⁵²; it consists of the exchange of 1 to 1.5 plasma volumes (5 L maximum), with 100% replacement by 4% human albumin solution. Plasmapheresis should preferably be conducted by a trained hemapheresis team using specifically designed machines. If no such team is available, plasmapheresis can be performed by intensivists on several machines designed for ICU continuous renal replacement (e.g., Spectra-Cobe, Prisma-Hospal), equipped with plasma exchange kits. The rate of plasma exchange is then lower, but these devices allow easy exchange of 1 plasma volume, with standard anticoagulation of the filter (whereas “classic” plasmapheresis is generally performed with citrate anticoagulation). The hemodynamic tolerance is usually correct, even if most patients require volume expansion because of a moderate hypotension after 60% or 70% of the plasma exchange (due to rapid removal of the osmotically active paraprotein).