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A 53-year-old patient presents with fatigue, night sweats and early satiety. Physical examination reveals an enlarged spleen (shown). A complete blood count (CBC) is remarkable for a white blood cell (WBC) count of 34,000/µL, with the differential showing blasts (3%), promyelocytes, myelocytes, basophils, eosinophils, and nucleated red blood cells (RBCs). The leukocyte alkaline phosphatase (LAP) score is 16, which is low.
Of the following pairings of a diagnosis with an associated cytogenetic abnormality, which is the most likely?
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Answer: C. Chronic myelogenous leukemia, t(9;22).
Chronic myelogenous (or myeloid) leukemia (CML) is one of the few malignancies characterized by a single genetic rearrangement. Chromosomes 9 and 22 reciprocally swap genetic material (shown), resulting in an elongated chromosome 9 and a characteristic shortened chromosome 22 referred to as the Philadelphia chromosome (Ph), which carries the BCR-ABL fusion gene.
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ABL is an oncogene that is usually translated into a tyrosine kinase that functions to control cell proliferation. The fusion gene BCR-ABL translates into a tyrosine kinase that is constitutively activated and results in uncontrolled cell proliferation and evasion of apoptosis. Cells divide continually but do not arrest their maturation process. The result is a "bone marrow picture in peripheral blood" that includes precursor cells as well as intermediate forms (shown). Cells are depleted of their enzymes, which is why the alkaline phosphatase is low in CML but not in leukemoid reactions. Decreased alkaline phosphatase activity in the granules from neutrophils of patients with CML is the result of decreased enzyme content in the immature forms and not a consequence of synthesis of catalytically defective enzyme.[1] The spleen may enlarge and encroach on the gastric body, resulting in focal pain and early satiety. The hypermetabolic activity also results in weight loss, fevers, and night sweats. High cell turnover can cause hyperuricemia.
The initial workup should include a CBC, a chemistry profile, measurement of the uric acid level, and bone marrow aspiration and biopsy (shown). Cytogenetic examination of the bone marrow should be performed to confirm the diagnosis and the stage or phase of the disease. Fluorescence in situ hybridization (FISH) testing can detect BCR-ABL in uncommon cases where Ph is negative in conjunction with regular cytogenetics. Reverse transcription polymerase chain reaction (RT-PCR) testing is usually also performed on diagnosis to provide a quantitative estimate of the burden of disease to follow during therapy.
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Answer: D. Imatinib mesylate.
At one time, allogeneic bone marrow transplant (BMT) was the first-line therapy for CML; however, with the advent of imatinib and other tyrosine kinase inhibitors (TKIs; mechanism of action shown), BMT has come to be considered third- or fourth-line therapy, except in specific patient subpopulations. The availability of TKIs has greatly improved patient survival; the 7-year overall survival for patients receiving imatinib has been reported to be 85%.[2] Imatinib was the first TKI developed for the treatment of CML and remains popular among hematologists as first-line therapy for CML. Second- and third-generation TKIs have been developed that are more potent than imatinib. A trend toward using second-generation TKIs in frontline treatment of CML is being noted, particularly in younger patients with high-risk disease.
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A 67-year-old man presents to the office with fatigue. He also reports recently experiencing easy bruisability and mild abdominal discomfort. Examination reveals a slightly ill-looking man with a few palpable cervical lymph nodes measuring 1-2 cm each, a palpable spleen about 3 cm below the left costal margin, and a few petechiae on his lower extremities (shown).
What is the most appropriate next step in the workup?
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Answer: C. CBC with examination of the peripheral smear for any abnormalities.
The patient's blood count reveals a hemoglobin level of 11.5 g/dL and a WBC count of 63,000/µL with 92% lymphocytes. The platelet count is 25,000/µL. The smear (shown) shows numerous mature-appearing lymphocytes with dense nuclei, anemia, and thrombocytopenia; it also shows the characteristic "smudge cell," which is an artifact of slide preparation causing disruption of the fragile lymphocytes in chronic lymphocytic leukemia (CLL). Before immunophenotyping became available, the peripheral blood morphology evaluation was generally considered sufficient for a diagnosis of CLL. Currently, however, flow cytometry is considered essential for demonstrating the clonality of the lymphocytes and confirming the diagnosis. Flow cytometry in this patient shows a clonal lymphocytic population that is positive for CD5, CD20, and CD23, thus confirming the diagnosis of CLL.
The same patient returns 4 weeks later with a rash (shown). A repeat CBC shows marked thrombocytopenia with a platelet count of 10,000/µL. A bone marrow biopsy reveals 30% involvement of marrow with neoplastic lymphocytes, but there also seems to be adequate active hematopoiesis present, and megakaryocytes are mildly increased.
What is the most appropriate next step?
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Answer: B. Start prednisone therapy.
Autoimmune thrombocytopenia (AIT) develops in 2-5% of cases of CLL. Autoimmune hemolytic anemia (AIHA) is another complication of CLL that is seen in as many as 10% of patients.[3] About one third of patients who have CLL with AIT also have AIHA (Evans syndrome). The diagnosis is generally made on clinical grounds when the bone marrow is not heavily involved with neoplastic cells and spleen size does not explain the severe thrombocytopenia. Marrow megakaryocytes are generally normal to increased in number. AIT or AIHA usually responds to treatment with steroids initially, but many patients relapse after treatment cessation. Other options include intravenous (IV) immunoglobulin, which can improve blood counts quickly, though often only transiently. Rituximab (anti-CD20) and, more recently, alemtuzumab (anti-CD52) have also been used for the treatment of autoimmune complications.[4,5]
Initially, the patient's condition improves with prednisone therapy, but then it starts to worsen over the following few months. He also gradually begins to experience more fatigue, a poorer appetite, and enlarging cervical and mediastinal lymphadenopathies. His splenomegaly has worsened, and by 6 months, his spleen is at the level of the umbilicus. At this point, the WBC count is 150,000/µL, the hemoglobin level is 10.5 g/dL, and the platelet count is 20,000/µL.
What is the most appropriate next step?
Image courtesy of Dr Karem Gharzeddine.
Answer: B. Discuss initiating chemotherapy with the patient.
Enlarging lymph nodes, worsening splenomegaly, and progressive marrow failure are evidence of disease progression and are indications for chemotherapy. Several regimens are in clinical use for treatment of CLL,[6] including fludarabine,[7] bendamustine, and alkylating agents. A few targeted/biologic agents have been introduced for use either alone or in combination with established chemotherapy.
Indications for treatment generally include the following[6]: progressive marrow failure (worsening of anemia or thrombocytopenia); massive or symptomatic splenomegaly or lymphadenopathy; AIHA or AIT that is poorly responsive to steroids or other standard therapies; significant constitutional symptoms, such as weight loss, fatigue, fevers, or night sweats; and progressive lymphocytosis with an increase of more than 50% over a 2-month period or an anticipated doubling time of less than 6 months (a particularly alarming finding).
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A 71-year-old man presents to the emergency department with fevers and a cough. Mild splenomegaly is noted. The CBC shows a hemoglobin level of 8.3 g/dL, a WBC count of 1000/µL, and a platelet count of 95,000/µL. A chest x-ray is obtained (shown).
What is the most appropriate next step?
Image courtesy of the National Institutes for Health (NIH).
Answer: D. Admit the patient for an infectious and hematologic workup.
The extensive bilateral infiltrates and pancytopenia in this elderly man are alarming. Careful examination of a peripheral smear reveals an excess of lymphocytes and numerous small projections coming off these lymphocytes (shown). This is typical of hairy cell leukemia, a rare form of chronic leukemia. Patients with hairy cell leukemia generally present with splenomegaly, leukopenia, and neutropenia. Bone marrow aspiration usually yields a "dry tap," and neoplastic cells in the marrow typically stain positive for tartrate-resistant acid phosphatase (TRAP). Cells are generally positive for B-cell markers such as CD19, CD20, CD22. They are negative for CD5 and CD23, and they can also express markers that are not typical for B cells (eg, CD11c, CD25 and CD103). In the majority of patients, the malignant cells carry BRAF mutation.
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Large granular lymphocyte (LGL) leukemia is similar to CLL in presentation. The lymphocyte count is typically elevated but only mildly so; accordingly, a high index of suspicion is required to make the diagnosis. LGL leukemia is typically indolent in its course, and advanced cases present with anemia or neutropenia. Patients with LGL leukemia are identified by their T-cell or natural killer (NK)-cell markers.[8] The median age at diagnosis for T-cell LGL leukemia is 60 years of age and the majority of LGL patients show a LGL count greater than 2.0 × 109/L.[9,10]
Image courtesy of Dr H Sayar.
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