Blast Crisis and Hyperleukocytosis

By: Nicole Messenger, MD

Faculty Reviewer: Chris Holthaus, MD

Let’s do a rapid review of blast crisis and its etiology, since some of this material hasn’t been reviewed since our days in medical school.  Let’s begin with the disease process that most commonly leads to blast crisis-- Chronic Myeloid Leukemia, CML for short.  CML is a myeloproliferative disorder associated with the Philadelphia chromosome [t(9;22)(q34;q11) and/or the BCR-ABL fusion gene, to be specific]. This genetic abnormality results in the formation of a unique gene product (BCR-ABL), which results in a constitutively active tyrosine kinase.

CML has three phases—chronic (stable) phase, accelerated phase, and blast crisis.  Given new tyrosine kinase inhibitory therapy, only 6% of patients embark on the accelerated phase of the disease that leads to blast crisis despite starting therapy during the chronic phase.  However, 10-15% of patients with CML alone will develop blast crisis. In roughly 30% of patients with CML, the lymphoid portion of the disease is the culprit for developing blast crisis. 
Per the World Health Organization, blast crisis is defined when one of the following occurs:

o    Greater than or equal to 20% of the peripheral blood or bone marrow is composed of blast cells (What is commonly identified in the Emergency Department)
o    Large clusters of blasts are observed in bone marrow biopsy
o    And evidence of extramedullary blastic infiltrates

Patients with CML have a 1% per year risk of progression toward blast crisis, therefore a diagnosis of CML is usually known prior to presentation in the emergency department for blast crisis.
Symptoms of disease progression to blast crisis include: night sweats, weight loss, bone pain, fevers, and symptomatic anemia; so do not forget these questions in review of systems regarding your CML patients.

Characteristic peripheral blood smear of chronic myeloid leukemia shows basophilia and granulocytosis with neutrophils and immature granulocytes.

Reproduced with permission from: McClatchey, KD, MD, DDS. Clinical Laboratory Medicine, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2002. Copyright ©2002 Lippincott Williams & Wilkins

Lab studies to collect in the Emergency Department for patients with the working diagnosis of blast crisis include CBC with Differential, glucose, and CMP for hepatic and renal functions
It is pertinent to recall that patients presenting in blast crisis can have serious complications such as fever, renal failure, and tumor lysis.  If you are concerned for tumor lysis, get IV fluids on board to help avoid renal failure secondary to deposits of uric acid, as well as to avoid hyperkalemia and hyperphosphatemia.  Tumor cells can hold 4-fold the amount of phosphorus, which when lysed may lead to hypocalcemia that will result in seizures. And remember, hyperkalemia can lead to arrhythmias and cardiac arrest!

Now let’s discuss a more serious complication—hyperleukocytosis and leukostasis.  Hyperleukocytosis is diagnosed empirically when a patient with leukemia has a white blood cell (WBC) count over 100 x 109/L (100,000/microL).  Leukostasis is the symptomatic diagnosis due to tissue hypoxia, most commonly respiratory or neurological distress, secondary to leukocytosis. One study found there is “not a good correlation between the threshold of WBC and/or blast count and the development of signs and symptoms of leukostasis”1.  Leukostasis is believed to stem from the increased production of WBC that increases viscosity in the microcirculation, leading to decreased perfusion of major organs.  To muddy the waters of diagnosis even more, 80% of these patients with hyperleukocytosis will be febrile from inflammatory processes and/or infection. This is why hyperleukocytosis and leukostasis should remain at the top of a physician’s differential. If left untreated, patients presenting in hyperleukocytosis have a mortality of 40% in one week.

Let’s imagine we have a patient with an active hematologic malignancy who presents febrile and in acute respiratory failure, now on 4L of nasal cannula. How should we initially approach this patient?

 First, obtain vitals-- stick a pulse oximeter on the patient-- especially if they are dyspneic.  Obtain a complete history and physical, do not forget to inquire about recent blood transfusions, as this increases the WBC count. Hyperleukocytosis/leukostasis should be a primary concern for this imaginary patient, so a CBC with differential is warranted, as well as CMP, PT/INR, PTT, and fibrinogen. Given the acute respiratory failure, one might consider obtaining and Arterial Blood Gas; here is the problem one will run into—the arterial pO2 will be falsely decreased by the large sum of WBCs’ metabolism.  PT/PTT and fibrinogen levels should also be noted as disseminated intravascular coagulation (DIC) is a common complication.  And to piggyback on the blast crisis work-up, you want to observe any renal failure and/or electrolyte abnormalities.  A chest X-ray should also be ordered if there are respiratory symptoms.  And for altered patients, a head CT should be performed.

Treatment focuses on supportive therapy and getting your Hematologist/Oncologists on board early for cytoreduction!  Optimize oxygenation and start IV fluids, but be cognizant to not overuse fluids in patients already in respiratory distress as this will exacerbate any pulmonary edema.  One study has shown hydroxyurea prior to chemotherapy to be beneficial.  The study titled Management of hyperleukocytosis, found, “standard care for acute hyperleukocytosis must include cytoreduction, proper supportive care, and prevention of tumor lysis. Hydration, alkalization, allopurinol, or urate oxidase should be started immediately. In patients with low platelet count of less than 20,000/mm(3), platelet transfusions should be given to prevent cerebral hemorrhage, as platelets do not add substantially to blood viscosity”.  Avoid blood transfusions as this will increase viscosity; if hemodynamically stable with hemoglobin of less than 7, it is recommended to transfuse to a hemoglobin value no greater than 10. Leukapheresis is an adjunct to the initial resuscitation of the patient with the above mentioned standard of care, but it only transiently decreases peripheral WBC load. Once the patient is stabilized, chemotherapy must be initiated, as it is the first-line treatment for hyperkeulocytosis2. 
For the asymptomatic patient with hyperleukocytosis, hydroxyurea is the first line agent. Not to be given to pregnant patients or patients breastfeeding, but for all others, hydroxyurea was found to decrease white blood cell counts 50 to 80% within the first 48 hours with doses of 50 to 100mg/kg daily.

G-band ideograms (left) and partial karyotype (right) of the CML-associated chromosome translocation t(9;22)(q34;q11.2). Breakpoints are indicated with arrows on the normal chromosome homologs. Translocated segments are framed on the der(9) and Ph ideograms. The translocation results in a slightly longer chromosome 9 [der(9)] and a shorter chromosome 22 [der(22)], which is termed the Philadelphia (Ph) chromosome.

Courtesy of Athena Cherry, PhD.

As previously mentioned, monitor platelets because reperfusion injury occurs commonly after WBC reduction and increases occurrence of intracranial hemorrhage; platelets should be greater than 20,000, and if not, platelet transfusion is warranted. And always be concerned for DIC and coagulation abnormalities in this patient population.  Once the patient is stabilized, use leukapheresis as the “bridging therapy” to the definitive therapy of chemoreduction agents like hydroxurea and chemotherapy(3).  Continue fluids as tumor lysis will be a complication with chemotherapy.

References:

1.    Uz, B. “A Medical Emergency: Leukostasis,” Global Journal of Hematology and Blood Transfusion. 2015.
2.    Ruggiero, Rizzo, Amato, and Riccardi, “Management of Hyperleukocytosis,” Curr Treat Options Oncol. February, 2016.
3.    Pham, HP and Schwart, J. “How We Approach a Patient with Symptoms of Leukostasis  Requiring Emergency Leukocytaphereis,” Transfusion. October, 2015.
4.    Uptodate: Blast Crisis and Hyperleukocytosis/Leukostasis.
5.    Tintinalli’s Emergency Medicine: A Comprehensive Study Guide 8th Edition. Tintinalli, et al. 2016.