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.