Annals of B Pod: Blast Crisis
/HISTORY OF PRESENT ILLNESS
The patient is a female in her early 20s who was referred to the emergency department (ED) by her primary care provider, who saw her earlier that day for knee pain. The patient has had pain in bilateral knees for the past two days and describes it as deep, aching, and constant. The pain is worse with ambulation and slightly improved with acetaminophen and ibuprofen. She denies any recent trauma. She has had some associated hand and ankle arthralgias as well. Earlier today, her primary care provider prescribed ketorolac and prednisone and ordered outpatient laboratory studies. She was then advised to immediately present to the ED after labs resulted and were noted to have a profoundly elevated white blood cell count. Review of systems at time of presentation to the ED is negative for headaches, vision changes, night sweats, weight loss, fever, chills, nausea, vomiting, chest pain, or dyspnea.
PAST MEDICAL HISTORY: Asthma, bipolar I disorder, post-traumatic stress disorder
PAST SURGICAL HISTORY: None
MEDICATIONS: Albuterol, cetirizine, vitamin D3
ALLERGIES: None
SOCIAL HISTORY: No tobacco or alcohol use. Smoke marijuana regularly.
PHYSICAL EXAM
Vitals: T 99.0 F HR 95 BP 123/88 RR 18 SpO2 99% on RA
The patient is a young female in no apparent distress, well-nourished without cachexia. Head, ears, eyes, nose, and throat exam reveals moist mucous membranes. Cardiopulmonary examination is unremarkable. Abdominal exam is benign without focal tenderness or distension. She has warm, dry skin without rash, petechiae, or ecchymoses. Musculoskeletal exam demonstrates no swelling, tenderness, or limitation of range of motion of bilateral knees. Neurologic exam reveals appropriate mental status, grossly intact cranial nerves, normal ambulation, and spontaneous movement of all four extremities.
DIAGNOSTICS
WBC 252 HGB 8.4 HCT 30.1 PLT 129
Differential: Myelocytes 10.5% | Metamyelocytes 3.0% | Bands 10% | Neutrophils 30.5% | Lymphocytes 4.5% | Monocytes 1.5% | Eosinophils 1.5% | Basophils 0.5% | Comments: noted to have 38% blasts on path review MCV 88.9 | MCH 25.8
Na 137 K 3.7 Cl 103 CO2 27 BUN 11 Crt 0.89 Glu 110 Mg 2.1 Phos 4.2
Haptoglobin <30 (44-215 mg/dL) LDH 1,753 ( 140-280 units/L) Uric acid 6.5 (3.8-8.7 mg/dL)
D dimer 6.31 CRP 24.8 (1-10 mg/L)
Fibrinogen 250 (218-406) INR 1.2, PTT 36.3
Hepatic function panel AST 50, bilirubin normal
Blood cultures and peripheral smear pending
Knee X rays revealed no joint effusion or evidence of acute bony abnormality
HOSPITAL COURSE
The bone marrow transplant (BMT) team had been pre-notified about the patient and admitted her to their service. They reviewed her peripheral smear and found it concerning for chronic myelogenous leukemia (CML) with blast crisis. She underwent bone marrow biopsy, flow cytometry, and chromosome analysis which were consistent with primary B-cell acute lymphoblastic leukemia, with positivity for the Philadelphia chromosome with BCR-ABL1 translocation t(9;22). She was started on hydroxyurea for cytoreduction; fluids for rehydration and hyperleukocytosis; Dasatinib for targeted therapy; steroids and allopurinol for tumor lysis syndrome prophylaxis; and bacterial, viral, and fungal antimicrobial prophylaxes.
It was at first uncertain whether this represented a de novo malignancy or whether it arose from underlying long-standing CML, however, further chart review revealed that the patient had actually had a leukocytosis with abnormal myeloid precursors for months to years, more consistent with primary CML. Lumbar puncture was performed to evaluate for malignancy and initiate intrathecal chemotherapy with methotrexate and hydrocortisone. The patient’s knee pain persisted throughout hospitalization and was thought to be due to her underlying malignancy. She was ultimately discharged after her hyperleukocytosis improved with a plan to continue scheduled chemotherapy and undergo evaluation for a bone marrow transplant.
DISCUSSION
Figure 1: Normal Hematopoiesis
Pathophysiology
Chronic myelogenous leukemia (CML) is a hematologic malignancy and myeloproliferative disorder that occurs due to a translocation between the long arms of chromosomes 9 and 22, resulting in the pathologic Philadelphia chromosome, so-named because it was discovered in Philadelphia. This translocation results in a fusion gene (BCR-ABL) that encodes a constitutively active tyrosine kinase known as the Bcr-Abl1 protein. [1,2] This protein causes the uncontrolled production of dysregulated, dysfunctional cells of myeloid lineage in various stages of development, particularly matured and maturing granulocytes (figure 1). Although almost all CML cases are associated with the Philadelphia chromosome, the Philadelphia chromosome can also be present in acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML), and its presence is not sufficient for definitive CML diagnosis. [2,3]
Epidemiology
CML accounts for approximately 15% of leukemia diagnoses in the Western Hemisphere,[2] with 1-2 cases per 100,000 people diagnosed annually.[4] Its prevalence is increasing due to improving survival rates with the development of more effective therapies in recent years.[2] CML is most common in adults with a median age at diagnosis of 66, and only 2% of cases are diagnosed in adolescents and children.[4,5] Risk factors for CML include exposure to ionizing radiation, gender (slightly more common in males), and older age.[6]
Clinical Presentation
Patients with CML present in one of three phases: chronic phase, accelerated phase, or blast phase. Ninety percent of patients with CML are diagnosed in the chronic phase, often incidentally due to an abnormal complete blood count performed for other reasons, though most do report at least one symptom at the time of diagnosis.[7,8] As the disease progresses, patients may enter the accelerated phase, and then the blast phase, which are diagnoses made using laboratory and pathology studies (table 1).[8,9] Patients in the accelerated phase and blast phase are much more likely to have treatment-resistant disease and a poorer prognosis.[8]
Table 1. Diagnostic criteria for CML-AP and CML-BP
Early in the disease course, patients may experience generalized symptoms such as malaise, weight loss, fever, and abdominal discomfort due to developing hepatosplenomegaly associated with extramedullary hematopoiesis.[8] As the disease becomes more advanced, patients are more likely to experience bone pain, lymphadenopathy, and skin infiltration.[2] Some of the more commonly reported symptoms at the time of CML diagnosis are summarized in table 2.[7] A variety of additional rare presentations of CML have been reported in the literature including spontaneous splenic rupture or infarct, avascular necrosis, intracranial hemorrhage, spontaneous soft tissue hematoma, and other symptomatic bleeding and ischemic conditions.[10–14]
Patients in blast phase may present with hyperleukocytosis (WBC count >50-100 x 109 /L) leading to leukostasis, which is a true oncologic emergency in which white blood cell infiltrates in the microvasculature cause tissue ischemia. The pathophysiologic mechanisms underlying leukostasis are not completely understood, but are thought to include increased blood viscosity as well as endothelial damage.[15] Symptoms of leukostasis can involve any organ system, most commonly the central nervous system, lungs, and kidneys, and may include cerebrovascular accident, confusion, coma, acute respiratory distress, and renal failure in addition to retinal hemorrhage, priapism, tinnitus, myocardial ischemia, bowel infarction, and venous thrombosis.[8,16] Eighty percent of patients presenting with leukostasis have fever, likely from heightened inflammation or concurrent infection.16
Diagnostic Workup
Patients with CML frequently present with leukocytosis ranging from 10-500 x 109 /L. Careful examination of the white blood cell differential is extremely important, since leukocytosis can easily be attributed to infection or inflammation. In CML, the differential will show a left-shift with predominance of neutrophils and the presence of bands, myelocytes, metamyelocytes, promyelocytes, and blasts. Absolute basophils or eosinophils may also be increased. Thrombocytosis or thrombocytopenia may be present, and anemia is present in about one-third of patients.[17] A peripheral smear is also helpful in the ED to identify abnormal cellular morphology. Ultimately, a bone marrow biopsy with advanced pathology and cytogenetic testing are necessary to make the diagnosis.[8] If hematologic malignancy is suspected in the ED, it is important to evaluate for secondary complications such as disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), bleeding from thrombocytopenia, and end-organ damage from leukostasis. An infectious workup may also be warranted, given that these patients are at higher risk for infection with dysfunctional circulating immune cells and possible functional asplenia.[16,18]
Treatment
Treatment of CML in the ED should focus on management of serious complications in consultation with hematology-oncology. The most common causes of death in patients with CML in blast phase are infection due to functional neutropenia, and hemorrhage due to thrombocytopenia or DIC.[16,21] Thus, aggressive evaluation and management of infectious sources should be undertaken, and transfusion of blood products should be discussed with hematology-oncology to define appropriate transfusion thresholds. In some cases, transfusion of blood products worsens hyperviscosity and should be avoided.[16]
In patients with hyperleukocytosis, cytoreduction should be initiated to mitigate end-organ damage from leukostasis.[16] Treatment options (other than induction chemotherapy) include hydroxyurea, intravenous fluids, and leukapheresis.[16,19,20] Hydroxyurea is a cytoreductive agent that serves as bridge to definitive therapy in reducing circulating leukocytes.[16,20] Fluids can be used for rehydration and decreasing blood viscosity. Leukapheresis can effectively lower the WBC count from 10-70% after just one treatment, but its effects on morbidity and mortality are uncertain.[19] In addition, leukapheresis involves multiple risks including anticoagulation, hypocalcemia, worsening of thrombocytopenia, and the need for central venous access, and as such, it is a treatment that can be considered but not routinely recommended.[16] Dexamethasone is also frequently used as an adjunct to reduce inflammatory effects.[16]
Definitive treatment for CML involves tyrosine kinase inhibitors (TKIs), which target the pathologic BCR-ABL tyrosine kinase through competitive inhibition at ATP binding sites.[2] The advent of this therapy in 1999 has revolutionized the treatment of CML and greatly improved its prognosis, reducing progression from CML chronic phase (CP) to CML blast phase(BP) from 20% annually to 1-3% annually.[16] Imatinib, one of the first TKIs to be developed, has been largely replaced by other agents such as nilotinib and dasatinib.[22] CML-BP often involves a combination of TKI and additional chemotherapy, and intrathecal prophylaxis is indicated given the high risk for occult central nervous system involvement and subsequent relapse.[16] Most patients who progress to CML-BP require bone marrow transplant.[16]
SUMMARY
Chronic myelogenous leukemia is a hematologic malignancy associated with the Philadelphia chromosome and the Bcr-Abl1 protein. Patient presentations are varied and can include constitutional symptoms, bleeding, leukostasis, DIC, and TLS. Diagnosis is made using CBC, peripheral smear, bone marrow biopsy and cytogenetic testing in conjunction with hematology/oncology. ED management focuses on complications, with ultimate treatment including tyrosine kinase inhibitors, chemotherapy, and bone marrow transplant.
AUTHORED BY LAUREN GILLESPIE, MD
Dr. Gillespie is a PGY-2 in Emergency Medicine at the University of Cincinnati
EDITING BY THE ANNALS OF B POD EDITORS
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