Hematologic Malignancies in the Intensive Care Unit

Published on 26/03/2015 by admin

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154 Hematologic Malignancies in the Intensive Care Unit

With the rapid improvement in chemotherapy, targeted therapy, and supportive care of hematology patients, almost all hematologic malignancies in children and adults are potentially curable with chemotherapy, either alone or in combination with immunotherapy or radiotherapy and sometimes bone marrow transplantation. If the malignancy is not curable, prolonged remission with acceptable quality of life is achievable for most patients. Nevertheless, delay in treatment of some aggressive malignancies can greatly jeopardize the chances of recovery for some acutely ill patients. In addition, intensivists may be confronted with unusual presentations of hematologic emergencies which they must learn to manage adequately.

image Emergency Management of Hematologic Malignancies in the Intensive Care Unit

Emergency Diagnosis

Emergency diagnosis of a hematologic malignancy is rarely necessary, and most patients with suspected or confirmed hematologic malignancies can be admitted directly to the hematology unit with simple supportive care (e.g., management of febrile neutropenia, transfusion if appropriate). Indeed, the specific care of patients diagnosed with acute leukemias or aggressive lymphomas should always be left to highly trained hematologists. For most of these patients, emergency initiation of induction chemotherapy is not required; chemotherapy can easily be delayed for 1 day or longer until an attending hematologist and cytologist can be reached and the necessary samples can be drawn and adequately processed.

In rare cases, patients present with life-threatening complications when no attending hematologist is available. Especially for leukemias, one should always try to obtain the following blood and marrow samples to allow for a precise diagnosis (i.e., cytologic characterization of the myeloid or lymphoid lineage, precise subtyping, and immunocytometric studies):

Clinical Situations Requiring Urgent Chemotherapy

A small number of patients are admitted directly to ICUs with life-threatening complications1 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:

image 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.46 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).710

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.

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.1618 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.