Blast Crisis: ED-focused management

Authors: Patrick C Ng, MD (EM Chief Resident, SAUSHEC Emergency Medicine Department) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC Emergency Medicine Department) // Editors: Jennifer Robertson, MD, MSEd and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Case 1

A 66-year-old male, recently diagnosed with chronic myelogenous leukemia (CML) presents with a sudden onset of pain and loss of vision in the left eye while eating lunch. He had been previously asymptomatic. He reports no relieving or exacerbating features. Labs were at baseline two weeks prior to this visit.

On exam, he has normal vital signs. His visual acuity reveals 20/200 OS and 20/40 OD with his corrective lenses. His exam is otherwise unremarkable.

Some standard labs are ordered, and his white blood cell count returns at 50 x 109/L. With progression of his symptoms despite supportive care, the patient is admitted for further management. MRI reveals enhancement of soft tissue are around the orbit and optic nerve of the left eye. He undergoes enucleation of the left eye. Histopathology reveals thickening of the choroid and infiltration of the choroid by blast cells. The working diagnosis of extramedullary blast crisis in CML is made and induction therapy is started1.

Case 2

A 58 year old female, with a history of hypertension and CML, on imatinib, presents to your ED with 2 weeks of generalized fatigue and a 10lb weight loss.  For the past 24 hours, she has started to experience left upper quadrant abdominal pain with decreased appetite. Her review of systems is positive for bilateral knee pain and fever with a Tmax of 101°F. She has never experienced this constellation of symptoms in the past and reports minimal relief with OTC antipyretics.

Vitals: T101°F, HR 100, BP 170/90, RR 18, Sat 100% on RA

Exam is positive for a palpable spleen approximately 3cm below the costal margin, tachycardia, and suprapubic pain.

Labs are significant for a white blood cell count of 40.4 x 109/L with 25% blasts, platelet count of 110 x 103/µL, Hb of 8g/dL, and a normal chemistry.  UA is positive for nitrite, leukocyte esterase and 2+bacteria.

The patient is started on IV fluids, antipyretics, and broad spectrum antibiotics. Hematology/Oncology service is consulted, and the patient is started on ponatinib for the suspected progression of her CML despite first generation tyrosine-kinase inhibitor therapy. She is admitted with continued treatment to the hematology/oncology service. While in the hospital, she underwent a bone marrow biopsy which revealed hypercellularity with a predominance of neutrophils, eosinophils, and basophils with many megakaryocytes. Peripheral smear revealed a myeloid cell predominance.

During her hospital stay, she showed improvement with continued antibiotic and tyrosine kinase inhibitor therapy. She underwent a hematopoietic cell transplant by hematology/oncology and was discharged from the hospital with continued outpatient therapy.

Introduction

Chronic myeloid leukemia (CML) is a hematological malignancy that affects the leukocyte cell linage. In essence, malignancies occur when cells have a reproductive advantage over others, with disruption in the balance of cell proliferation and cell death2. In CML, this balance of cell proliferation and cell death is disrupted secondary to a reciprocal translocation between chromosome 9 and 22, t(9:22)(q34;q11), also known as the Philadelphia (Ph) chromosome. These chromosomes contain the BCR and ABL genes. The translocation forms a BCR-ABL gene which is a tyrosine kinase. This ultimately leads to an increase in myeloid cells in the blood3.

There are three phases of CML: Chronic, Accelerated and Blast, shown below in Figure 1. Approximately 90% of patients present in the chronic phase3. Blast phase is a poor prognostic marker. According to some reports, the median survival after diagnosis of blast crisis ranges from 7-11 months and that patients with 20%-29% blasts at diagnosis have a better prognosis than those with >30%4. Typically, patients present in the chronic phase and are diagnosed with routine blood testing. CML can progress to the accelerated phase, followed by the blast phase. The disease is on a continuum and nonspecific characteristics of each phase are summarized in Table 1. Many of the symptoms are nonspecific, especially in the chronic and accelerated phases. The blast phase may present with signs/symptoms similar to infection.

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CML Phase Chronic Accelerated Blast
Onset Indolent <1 year <6months
Signs/Symptoms Often asymptomatic, Fatigue, Decreased Appetite, Abdominal Pain/Fullness Same as Chronic Phase +/-Bone pain Same as accelerated phase+/- symptoms consistent with infection
Characteristic Clinical Findings Hepato/Splenomegaly Hepato/Splenomegaly unresponsive to treatment

 

Fever not otherwise explained

 

Bruising

 

Same as accelerated phase +/- Bleeding, Infection

 

Symptoms refractory to treatment

Laboratory Abnormalities Including Peripheral Smear Leukocytosis, Anemia, Thrombocytosis Leukocytosis(>50 x 109/L)

Anemia (Hct <25%)

Thrombocytopenia (<100 x 109/L) or

Thrombocytosis (>1,000 x 109/L)

Blasts (≥10%)

Basophils (≥20%)

Thrombocytopenia(<100 x 109/L)

 

≥20% Blasts

 

Bone Marrow Aspirate Characteristics Hypercellular Hypercellular

≥10% Blasts

Basophils

Same as accelerated +/-Megakaryocytes

≥20% Blasts

 

Table 1: Characteristics of CML phases,4,5,6,7,8

What are the key ED studies?

When the progression of CML is suspected in the ED, key studies to obtain include the CBC with differential, peripheral smear, chemistry, magnesium, coags, LFTs, lactate, uric acid, LDH, and phosphorous. As seen in Table 1, the diagnosis can be difficult due to the often vague symptoms, and lab abnormalities that are required for diagnosis confirmation. Patients that carry a diagnosis of CML can progress to the accelerated/blast phase despite being on treatment. CBC and differential with smear are important to obtain to determine whether or not a leukocytosis with a left shift is present, which can help you and your consultants narrow in on the diagnosis. Additionally, patients can present with varying degrees of platelet abnormalities and anemia, both of which may require specific interventions. It is important to consider these possible abnormalities as procedures such as bone marrow aspiration/biopsy can pose a significant bleeding risk.

The response to treatment and progression of CML is monitored by three different responses: hematologic, cytogenic, and molecular. In the ED, we can assess the hematologic changes in these patients with the labs mentioned above. Cytogenic and molecular testing are out of the scope of the ED provider and will be assessed by our consultants.

Additionally, infection can accompany progression of this disease. Based on the patient’s presentation and lab results, further workup (CXR, Blood cultures, UA, etc) and treatment with appropriate fluid resuscitation and antibiotics should be considered and discussed with the oncology team. Patients with documented fever will likely warrant broad-spectrum antibiotics. The ED provider must have a high degree of suspicion for infection in febrile patients presenting in blast crisis, as patients can be functionally asplenic. The proliferation of malignant cells in CML, particularly in the accelerated/blast phases, can lead to damage of the spleen secondary to splenic congestion and even splenic rupture5.

With the rapid proliferation of cell lines, patients may present with signs of end organ damage, likely secondary to hyperviscosity6-7, which can lead to end organ dysfunction and electrolyte abnormalities. Symptoms include but are not limited to bleeding, ocular, neurological, and cardiovascular problems8.

On a case by case basis, targeted diagnostics including labs and imaging may be indicated. There are rare presentations of blast crisis, particularly when there is an infiltration of leukemic blasts in areas other than the bone marrow, called extramedullary blast crisis9-12. Various case reports that describe extramedullary blast crisis include: presenting in the scalp, in the paravertebral area causing spinal cord compression, as leukemic ascites with liver disease and coagulopathy, in the eye with pain and vision changes eventually leading to enucleation, as an initial presentation with lymphadenopathy, with palpitations and dyspnea, with an osteolytic lesion presenting with leg pain, and as an osteolytic bone lesion leading to a pathologic fracture12-17. Although rare, extramedullary blast crisis can occur. However, this form is difficult to diagnose and requires oncology consultation.

Management

As seen, the clinical presentation of CML can vary widely; however, the treatment is relatively consistent. The ED management requires initial resuscitation and stabilization. Assessment for infection and hyperviscosity syndrome is required, as these account for significant mortality. Hyperviscosity syndrome can be treated with plasmapheresis, plateletpheresis, or phlebotomy. For a further read on this dangerous manifestation, please see http://www.emdocs.net/hyperviscosity-syndrome/.

The mainstay of oncologic therapy is with tyrosine-kinase inhibitors, with imatinib traditionally serving as the first line18. Patients not responding to initial dosing may be given a trial of an increased dose of imatinib. According to a recent survey, due to improved methods of disease monitoring and new generation tyrosine-kinase inhibitors, the use of imatinib as a first line agent has decreased. The use of newer generation tyrosine kinase inhibitors such as nilotinib/dasatinib has replaced imatinib as a first line agent according to several reports19-20. In patients that progress to blast crisis despite therapy, initial stabilization and resuscitation depending on the clinical presentation is indicated. Early consultation with a hematologist/oncologist is indicated as many of these patients will go on to combination chemotherapy with tyrosine-kinase therapy, and/or hematopoetic cell transplantation18-20.

Summary

-CML is a myeloproliferative disorder that can present at any age, but typically presents in the 6th decade of life

-CML has three phases: Chronic (most common), Accelerated, and Blast

-Blast phase is a poor prognostic factor

-Blast phase can present in a variety of ways including but not limited to eye pain, vision changes, neurologic complaints, joint pain, and bleeding. The emergency provider must maintain a high suspicion for this diagnosis, particularly in patients that carry a diagnosis of CML, although these can serve as initial presentations of the disease as well

-Blast phase can present in conjunction with other pathology including but not limited to fractures and infections. The emergency provider must be aware of this key point to properly address these pathologies in the initial resuscitation and management of the patient.

-Tyrosine kinase inhibitors serve as the first line of treatment for CML, those progressing to later phases may require other specialized therapy such as combination therapy or cell transplantation that will require expert consultation with a hematologist/oncologist.

 

References/Further Reading

  1. Gulati R, Alkhatib Y, Donthireddy V, Felicella MM, Menon MP, Inamdar KV. Isolated Ocular Manifestation of Relapsed Chronic Myelogenous Leukemia Presenting as Myeloid Blast Crisis in a Patient on Imatinib Therapy: A Case Report and Review of the Literature. Case Rep Pathol 2015:380451.
  2. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancerbase no.5, version 2.0. Available at: http://citeseerx.ist.psu.edu Last accessed 14July2016.
  3. Thora NK, Gundeti S, Linga VG, Coca P, Tara RP, Raghunadharao. Imatinib mesylate as first-line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis. Indian Journal of Cancer 2014 51(1):5-9.
  4. Hehlmann R. How I treat CML blast crisis. Blood 2012 120:737-747.
  5. Jafferbhoy S, Chantry A, Atkey N, Turner D, Wyld L. Spontaneous splenic rupture: an unusual presentation of CML. BMJ Case Rep 2011 Mar 24;2011.
  6. Druker, BJ. Translation of the Philadelphia chromosome into therapy of CML. Blood 2008 112:4808-4817.
  7. Faderl S, Kantarjian HM, Talpaz M. Chronic Myelogenous Leukemia: Update of Biology and Treatment. Oncology 1999 Feb;13(2):169-80.
  8. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost 2003 Oct;29(5):467-71.
  9. Jabbour E, Kantarjian H, O’Brien S, Rios MB, Abruzzo L, Verstovsek S et al. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 2006 107:480-482.
  10. Besa E. Chronic Myelogenous Leukemia. Medscape. Available at: http://emedicine.medscape.com/article/199425 Last accessed: 14July2016
  11. Granatowicz A, Piatek C, Moschiano E, El-Hemaidi I, Armitage JD, Akhtari M. An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians. Korean J Fam Med 2015 Sep;36(5):197-202.
  12. Sahu KK, Malhotra P, Uthamalingam P, Prakash G, Bal A, Varma N, Varma SC. Chronic Myeloid Leukemia with Extramedullary Blast Crisis: Two Usual Sites with Review of Literature. Indian J Hematol Blood Transfus 2016 Jun;32:89-95.
  13. Said MR, Yap E, Jamaluddin WF, Wahid FS, Shuib S. A case of chronic myeloid leukaemia in blast transformation with leukemic ascities. Med J Malayasia 2016 Apr;71(2):85-7.
  14. Ai DI, Liu W, Lu G, Patel KP, Chen Zl. Extramedullary blast crisis as initial presentation in chronic myeloid leukemia with the e1a2 BCR-ABL1 transcript: A case report. Mol Clin Oncol 2015 Nov;3(6):1319-1322.
  15. Zeng DF, Chang C, Li JP, Kong PY, Zhang X, Gao L. Extramedullary T-lymphoblastic blast crisis in chronic myelogenous leukemia: A case report of successful diagnosis and treatment. Exp Ther Med 2015 Mar;9(3):850-852.
  16. Tsukamoto S, Ota S, Ohwada C, Takeda Y, Takeuchi M, Sakaida E, et al. Extramedullary blast crisis of chronic myelogenous leukemia as an initial presentation. Leuk Res Rep 2013 Aug 13;2(2):67-69.
  17. Yu HH, Lu MY, Lin DT, Lin KH, Tang JL, Jou ST. Pathological fracture as a manifestation of extramedullary blast crisis in chronic myelogenous leukemia: a report of one case. Acta Paediatr Taiwan 2006 May-Jun;47(3):150-4.
  18. Kantarjian HM, Larson RA, Cortes JE, Deering KL, Mauro MJ. Current Practices in the Management of Chronic Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 2013 Feb; 13(1):48-54.
  19. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Labo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010 Jun 17;362(24):2251.
  20. Axdorph U, Stenke L, Grimfors G, Carneskog J, Hansen J, Linder O et al. Intensive chemotherapy in patients with chronic myelogenous leukaemia (CML) in accelerated or blastic phase-a report from the Swedish CML Group. Br J Haematol 2002 Sep;118(4):1048-54.

 

 

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