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CHAPTER 93 designation HCL has become universally accepted as the name of this
lymphocytic neoplasm, characterized by infiltration of the marrow by
HAIRY CELL LEUKEMIA malignant B-lymphocytes of a specific immunophenotype (see “Labo-
ratory Features” below), often accompanied by reticular fibrosis, sple-
nomegaly, anemia, thrombocytopenia, neutropenia, monocytopenia,
and usually pancytopenia. Occasionally, there is an elevated total white
Michael R. Grever and Gerard Lozanski cell count because of the abundance of malignant B-lymphocytes in the
blood. Splenectomy was the sole therapeutic approach until the early
observations of responses secondary to α-interferon and the purine ana-
2,3
SUMMARY logues. Whereas splenectomy improved the blood counts, the impact
of this intervention was temporary, resulting in improvement of symp-
toms related to splenic sequestration. Most standard chemotherapy was
Hairy cell leukemia (HCL) is an uncommon form of adult chronic B-cell leu- ineffective and poorly tolerated. In 1984, Quesada described the bene-
kemia. Whereas the cell of origin is uncertain, at diagnosis the characteristic fits of daily α-interferon in achieving responses in seven patients with
leukemic cells are found in the marrow, the blood, and the spleen. Patients progressive HCL. Three patients achieved a complete response, with
2
present with fatigue, infections, and many have splenomegaly. They are often the remaining four having partial responses. Extensive description of
pancytopenic, or may have isolated cytopenias, and usually have monocytope- the effects of α-interferon on marrow showed improvement in granu-
nia. The leukemic cell in classic hairy cell leukemia (HCL-c) has a characteristic lopoiesis associated with increases in the number of both circulating
immunophenotypic profile (CD11c+, CD19+, CD20+[bright], CD22+, CD25+, granulocytes and platelets. While this approach was heralded as a major
CD103+, and CD123+ and CD27−). A variant of hairy cell leukemia (HCL-v), achievement in treating this disease, other opportunities emerged in the
which occurs less frequently, has been identified as a separate entity. A genetic same time frame.
mutation, BRAF V600E, has been identified in the majority of patients with the Grever and colleagues demonstrated that low-dose pentostatin was
classic form of this disease, but is not present in the variant. This mutation is effective in achieving responses in patients with far-advanced low-grade
4,5
B-cell malignancy. Spiers reported the initial response of HCL to pen-
also present in the hematopoietic stem cells of patients with HCL-c. tostatin in a limited number of patients, which was followed by a larger
3
HCL is characterized by impaired marrow function and immunity leading study with a complete remission rate of 59 percent. Kraut and col-
6
to a high incidence of infectious complications. Both pentostatin and cladrib- leagues subsequently showed that low-dose, less-intense, intermittent
ine are effective in achieving durable complete remissions. Long-term stud- pentostatin produced a higher complete remission rate (approximately
ies demonstrate prolonged survival of patients, but the disease-free survival 89 percent) in patients with HCL. Others confirmed these findings, and
7
8
curves do not plateau suggesting that the disease is not cured but subject to a large prospective randomized trial of pentostatin versus α-interferon
relapse. Survival has been markedly improved with the introduction of purine solidified that frontline therapy should be based upon a purine ana-
9
nucleoside analogues and is estimated to be 90 percent at 5-year followup. logue. Piro and colleagues reported that cladribine produced complete
10
When patients relapse, high-quality remissions can be achieved with salvage responses in 11 of 12 patients with this disease. Numerous trials with
therapy. cladribine confirmed that a single course of therapy was equally capa-
ble of inducing a high percentage of long-term complete responses. 11,12
However, the initial trials with cladribine excluded patients with an
active infection. 10,11 Several studies using cladribine aimed at optimizing
DEFINITION AND HISTORY the remission rate and attempting to reduce myelosuppression showed
that either 5 to 7 days of intravenous administration or subcutaneous
Cases of malignant diseases involving marrow that probably represented injection produced responses, but these alternate approaches did not
examples of hairy cell leukemia (HCL) were reported through the first consistently reduce the risks for febrile neutropenia. 13–15 In contrast,
half of the 20th century and designated by such terms as “lymphoid the reported frequency of febrile neutropenia was less in a study using
9
fibrosis.” They had features characteristic of HCL including marrow intermittent administration of pentostatin compared to those reported
10
replacement by mononuclear cells, marrow fibrosis, splenomegaly and with cladribine. Consequently, either purine nucleoside analogue is
anemia and thrombocytopenia. In 1958, Bouruncle, Wiseman, and now used to induce remission.
Doan described this constellation of findings in a group of patients. At In patients with an active infection, it is advisable to control the
1
that time there was no means to characterize the immunophenotype of infection before initiating immunosuppressive chemotherapy. However,
malignant lymphoid cells and they called the disease “leukemic reticu- if this is not possible then administration of either pentostatin alone or
loendotheliosis.” In 1966, Schrek and Donnelly, described the distinc- following α-interferon may be effective in controlling the underlying dis-
9,16
tive feature of cytoplasmic projections that were evident on the blood ease. If α-interferon is initially used to improve the neutrophil count
cells in two cases of this disorder. They called these “hairy” cells. The and control the leukemia, the subsequent use of pentostatin to achieve
1A
a complete remission is not compromised. Therefore, some investigators
have initially treated patients with HCL complicated by infection with
α-interferon, which was followed by pentostatin in an effort to reduce
16
infectious complications. While the use of filgrastim does reduce the
Acronyms and Abbreviations: HCL, hairy cell leukemia; HCL-c, classic HCL; HCL-v, degree and the duration of neutropenia, it does not reduce the number
variant of HCL; IHC, immunohistochemical stains; IL-2, interleukin-2; MRD, minimal of febrile episodes in patients being treated with cladribine, in com-
residual disease; SEER, Surveillance, Epidemiology, and End Results Program; SIR, parison to historical controls. However, it may be helpful in treating
17
standardized incidence ratio; TGF, transforming growth factor; TRAP, tartrate-resis- serious infections in neutropenic patients with HCL who are in a pre-
tant acid phosphatase; WHO, World Health Organization. carious medical condition. The optimal management of actively infected
patients with HCL requiring treatment is still challenging.

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