Case study 34.1

A 52-year-old Caucasian man is referred to you with abnormal blood counts. The white blood cell (WBC) count is 3000/μl, absolute neutrophil count (ANC) 1800/μl, hemoglobin 11 g/dl, and platelet count 130,000/μl. Further work-up reveals an enlarged spleen of 14.5 cm. The patient continues to work full-time as a bank manager. He denies B-symptoms or recurrent infections.

1. All of the following statements with regard to the diagnosis of hairy cell leukemia (HCL) are true EXCEPT:

Bone marrow examination usually shows a hypercellular marrow with increased reticulin fibrosis, mast cells, and absence of blasts
Monocytopenia is seen in almost all cases
Flow cytometry is negative for CD25 and CD22
There is absolutely no specific immunophenotypic marker for the diagnosis of HCL
Immunohistochemistry (IHC) is positive for DBA.44, TRAP, and ANXA1

HCL is a rare B-cell lymphoproliferative neoplasm that represents approximately 2% of all leukemias and affects 600–800 individuals annually in the United States. HCL is more common in Caucasians than African Americans and is more common in males by a ratio of 4:1. The median age at disease onset is 52 years. HCL is characterized by clonal proliferation of small, mature lymphocytes with classic “hair-like” cytoplasmic projections that accumulate in the peripheral blood, bone marrow, and spleen (Figure 34.1). This leads to decreased production of normal hematopoietic elements, causing anemia, thrombocytopenia, and neutropenia and monocytopenia. Splenomegaly is usually present and may be massive; however, lymphadenopathy is rare except in relapsed disease. Patients typically present with either incidental or symptomatic cytopenias or abdominal symptoms from splenomegaly. Leukocytosis is unusual, and most patients (60–80%) are pancytopenic at diagnosis. On bone marrow examination, the marrow is typically hypercellular with diffusely infiltrating hairy cells, and abundant cytoplasm surrounding nuclei may give cells a “fried-egg” appearance. There is often increased reticulin fibrosis (due to hairy cell infiltration), and there may also be an increased number of bone marrow mast cells. Blasts are not increased. Immunophenotyping by flow cytometry is an important, confirmatory test for the diagnosis of HCL, which has a characteristic immunophenotypic profile consisting of both mature B cell markers (CD19, CD20, and CD22) and aberrant expression of non-B-cell markers (CD11c, CD25, CD103, and CD123). However, there is no one marker or combination of markers that is 100% specific for the disease. Immunohistochemical stains for DBA.44, TRAP, and ANXA1 are typically positive in HCL but have been largely replaced by flow cytometry.

Figure 34.1 Hairy cells with classic circumferential, hairlike cytoplasmic projections. (Color plate 34.1)

2. All of the following neoplasms are considered in the differential diagnosis of patients presenting with splenomegaly and B-cell lymphoid aggregates in the bone marrow EXCEPT:

Splenic marginal zone lymphoma (SMZL)
Prolymphocytic leukemia (PLL)
Chronic lymphocytic leukemia (CLL)
HCL variant (HCL-v)
Primary myelofibrosis (PMF)

Primary myelofibrosis is a myeloid malignancy, and while it may cause splenomegaly it would not result in lymphoid aggregates in the bone marrow. See Table 34.1 for characteristics of A–D in relation to HCL.

Table 34.1 Characteristics of various neoplasms in relation to hairy cell leukemia (HCL).

3. The bone marrow biopsy of the patient presented in Question 1 shows a hypercellular marrow, but the marrow was inaspirable (a “dry tap”). Reticulin stain shows 2+ fibrosis surrounding hairy cells. Both flow cytometry on the peripheral blood and IHC on the marrow are consistent with the diagnosis of HCL. Should this patient be treated or observed?

This patient should be observed. Many patients with HCL are asymptomatic and can be observed for months to years before requiring treatment. HCL is typically idolent and slowly progressive, and there is no clear benefit to early treatment. Patients should be treated only when they become symptomatic or develop significant cytopenias. Typical indications for the treatment of HCL include an ANC <1000/μl, symptomatic anemia with hemoglobin <11 g/dl, and platelet count <100,000/μl. Symptomatic splenomegaly—early satiety, abdominal fullness and discomfort, and weight loss—is also an indication for treatment. Bulky lymphadenopathy at initial presentation is rare, and other diagnostic possibilities should be considered if present. Constitutional symptoms, such as fever and night sweats, should also prompt consideration of treatment after infection is ruled out. Infection should always be suspected and treated appropriately in a febrile patient with HCL; bacterial infections are most common, but opportunistic infections can occur as well.

Case study 34.2

A 35-year-old woman with HCL presents for routine evaluation. She has been observed without therapy since diagnosis about 18 months ago. Now, she reports new onset of fatigue and early satiety. The most recent complete blood count shows a WBC of 1300/μl, ANC of 800/μl, hemoglobin of 9 g/dl, and platelet count of 80,000/μl. Further work-up reveals an enlarged spleen of 18.0 cm. The diagnostic bone marrow biopsy, performed 18 months ago, was consistent with HCL.

1. Should the bone marrow examination be repeated prior to the initiation of therapy?

No. This patient’s clinical course is consistent with the natural history of HCL, and the bone marrow biopsy does not need to be repeated prior to treatment unless the initial diagnosis was in question or there is suspicion of another hematologic problem.

2. What is the best therapeutic strategy for this patient with symptomatic HCL?

Cladribine or pentostatin
Cladribine plus rituximab
Pentostatin plus rituximab
Cladribine plus granulocyte colony-stimulating factor (G-CSF)
Interferon-alpha
Splenectomy and transfusion support

Single-agent therapy with a purine analog, either cladribine (2-CdA) or pentostatin, is standard front-line therapy in patients with symptomatic HCL. Cladribine and pentostatin are purine analogs that interfere with normal purine metabolism. Mechanistically, cladribine is resistant to adenosine deaminase (ADA), and pentostatin directly inhibits ADA. The end result of both agents is the accumulation of toxic deoxynucleotides in lymphoid cells, which can cause DNA double-strand breaks and disrupt successful DNA synthesis and repair mechanisms. Both agents are highly effective in HCL, but cladribine is usually preferred given its safety profile and tolerability as well as the convenience of administration (given over a single cycle) compared to pentostatin (which is given repeatedly over several cycles). Both agents induce a durable complete remission (CR) in almost all patients with classical HCL, regardless of the extent or bulk of disease, and have similar long-term survival rates (approaching 90% or higher). Clinical trials showing the remarkable effectiveness of a single cycle of cladribine were first reported in the early 1990s. Several large studies have shown CR rates of at least 80–90% (with most other patients achieving a partial response) and 4-year progression-free survival (PFS) and overall survival (OS) of approximately 70–80% and 85–95%, respectively. Furthermore, some of these studies had very long follow-up and demonstrated 12-year OS rates of 80–90% (Figure 34.2). Pentostatin has similar response rates and is an acceptable alternative to cladribine. The dosing schedule of pentostatin has varied across clinical trials, but it is commonly given at 4 mg/kg intravenously every 2 weeks until maximal response (usually around six to eight cycles of treatment). Rituximab has been successfully combined with cladribine in clinical trials, and it may play an important role in relapsed disease. However, it is not currently indicated as part of front-line therapy. A phase II study by Ravandi and coworkers evaluated cladribine followed one month later by eight weekly doses of rituximab in newly diagnosed patients, and while the regimen was well tolerated, remission rates with cladribine alone were excellent and it is not known if the sequential addition of rituximab improves OS (endpoint not yet reached). Coadministration of G-CSF with cladribine decreases the length of neutropenia but does not affect the incidence or duration of febrile neutropenia or rates of hospitalization, and thus is not routinely recommended. Interferon-alpha (IFNα) is active in HCL and can improve the peripheral blood counts, although achievement of CR is uncommon and there is usually residual splenic and marrow involvement even if it is continued indefinitely. IFNα is rarely used in the upfront setting given the side effects (e.g., flulike symptoms and depression) and the superiority of purine analog therapy. While splenectomy was the first known treatment for HCL and can temporarily improve the peripheral blood counts in most patients for about 1–2 years, it is no longer indicated except for splenic rupture or as salvage in patients with multiply relapsed or refractory disease and no other treatment options.

Figure 34.2 Overall survival curve for 86 patients treated with cladribine (26 patients were previously treated). Dotted lines represent the 95% confidence interval. (Source: Chadha P, Rademaker AW, Mendiratta P, et al. Blood 2005;106:241–246. Reproduced with permission of the American Society of Hematology).

3. A decision to initiate therapy with cladribine is made for this patient. What is the optimal route and schedule for the administration of cladribine? How do you manage the fever that commonly occurs after cladribine?

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34: Hairy Cell Leukemia

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