Minimal residual disease in HCL 29
for chronic lymphocytic leukemia [CLL]) [12]. It is a
Summary of issues related to assessment of
human B lymphocyte-restricted differentiation phos-
minimal residual disease in hairy cell leukemia
phoprotein located on precursor and mature B
The prognostic implications of detectable MRD after lymphocytes in addition to indolent non-Hodgkin
therapy for HCL are unfortunately confounded by lymphomas (NHL) [13–15]. Upregulation of CD20
several factors: (1) variability in sensitivity of the expression has been demonstrated with use of
various techniques used to assess MRD, with FC cytokines such as granulocyte-macrophage colony
appearing to be the most informative and practical, stimulating factor or IFN-a [16].
(2) nonuniformity of the criteria used to define Rituximab is a high affinity chimeric IgG1 k MoAb
MRD, (3) variability in timing of MRD assessments which contains murine light- and heavy-chain vari-
after therapy, (4) limited numbers of patients in able region sequences with human constant region
comparative groups, (5) limited duration of observa- sequences. It directly induces apoptosis in addition
tion period in some series, and (6) variability in both to complement- and antibody-mediated cellular
detection of disease recurrence and time to retreat- cytotoxicity [14,17,18]. Initial clinical trials of
ment owing to the relatively indolent nature of the standard dose rituximab in previously treated CLL
disease. However, the preponderance of the data were disappointing. The low response rates were
suggests that persistence of MRD after therapy with attributed to the decreased expression of surface
nucleoside analogs is predictive for eventual disease CD20 compared with low grade NHL. Clinical trials
recurrence, further suggesting that interventions to of dose escalated or dose intensive rituximab in
eradicate MRD may improve outcome. relapsed or refractory CLL showed improvements in
the response rates predominantly in the form of
partial remissions [19,20]. However, when rituximab
Monoclonal antibody therapy for eradication of
was administered in combination with chemotherapy
minimal residual disease
such as fludarabine or fludarabine with cyclopho-
Postremission consolidation therapy for MRD de- sphamide, the outcome was significantly superior
tected after achievement of CR by conventional than with the chemotherapy alone [21,22].
criteria has been limited by the cumulative myelo- Several clinical trials have been conducted using
suppressive and immunosuppressive effects of single agent rituximab as therapy for previously
2-CdA. The severe and prolonged CD4 lymphocy- treated HCL with active disease (Table II) [23–27].
topenia can lead to opportunistic infections. Alter- The possible reasons for the differential activity of
natively, persistence of MRD after treatment with rituximab observed in these clinical trials include
DCF is unlikely to be eradicated by prolonged differences in disease burden (more extensive mar-
administration of this agent after achievement of row involvement was predictor for lower probability
CR. Alternative strategies to eradicate MRD include of response), dosing schema utilized (e.g. 4 versus 8
therapy with monoclonal antibodies (MoAbs) direc- weeks of therapy), elevated soluble CD20 [28] levels
ted against antigens on the surface of HCs. The resulting in antibody neutralization, and/or IgG FC-g
CD20 antigen is highly expressed on HCs receptor polymorphisms [29]. Consideration should
(312610
9
/L molecules per cell) compared with be given to include measurements of soluble CD20,
other leukemias (e.g. 65610
9
/L molecules per cell rituximab, and CD20/rituximab complexes in the
design of future clinical trials of this agent for HCL.
The use of rituximab to eradicate MRD after
Table I. MRD by IHC after 2-CdA or DCF [11].
nucleoside analog therapy for HCL has been
N (%)
MRD No MRD p-value
Table II. Rituximab in relapsed/refractory hairy cell leukemia.
Incidence
No. of CR PR OR
2-CdA (3 mos) 5/39 (13) 34/39 (87) 0.21
Study N weeks* (%) (%) (%)
DCF (6 mos) 7/27 (26) 20/27 (74)
Relapse rate [time of relapse, mos] Nieva et al. [23] 24 4 13 13 26
2-CdA 2/5 (40) [24, 25] 3/24 (9) [NA] NA Hagberg and Lundholm [24] 11 4 55
{
10 64
DCF 4/7 (57) 0/20 (0) Lauria et al. [25] 10 4 10 40 50
[18, 21, 44, 59] Angelopoulou et al. [26] 11 6 33 34 67
Overall 6/12 (50) 3/54 (6) Thomas et al. [27] 15 8–12 66 13 80
% 4-year RFS 55 (+15) 88 (+6) 0.0025
No., number; CR, complete remission; PR, partial response; OR,
MRD, minimal residual disease; IHC, immunohistochemistry; overall response.
No, number; 2-CdA, cladribine; DCF, deoxycoformycin; mos, *Rituximab 375 mg/m
2
intravenously.
months; NA, not available; RFS, relapse-free survival
{
CR rate 33% in 3 de novo HCL cases.
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