28 D. A. Thomas et al.
in the51% category. The MRD levels appeared in splenomegaly, and BM cytoreduction. The ki-
stable over a 24-month observation period except in netics of sIL-2R levels vary with therapy; normal-
cases with higher proportion of MRD from the start. ization occurs within 2–3 weeks of therapy with 2-
Matutes et al. [3] studied the incidence of CdA, within 4–6 months for DCF, and within 12
detectable MRD by FC in a cohort of patients with months for interferon-a (IFN-a). Increases in the
HCL (n¼23) in CR after therapy with deoxycofor- levels of sIL-2R may precede manifestation of
mycin (DCF). Peripheral blood (PB) and BM overt disease and could be assessed in conjunc-
samples collected at variable time points (median of tion with other MRD assessments in order to develop
10 months) were assessed for expression of CD3, an algorithm for monitoring and intervention; no
CD22, CD11c, CD25, HC2, and CD103. The such prospective studies have been conducted to
incidence of detectable MRD either in the blood, date.
marrow or both sites overall was 43%. Despite the
long-term follow-up (median 72 months), no sig-
Clinical relevance of minimal residual disease
nificant correlation was noted between the presence
in hairy cell leukemia
of MRD and subsequent relapse, owing to the usual
limitations encountered when analyzing outcomes in The timing of marrow assessments may influence the
a small number of patients. interpretation of outcomes based on MRD status.
Bengio et al. [4] compared the use of IHC (L26 Bastie et al. [9] assessed serial BMs by IHC staining
[CD20], DBA.44) and FC (CD20, CD22, CD25, with DBA.44 at 2–4, 6, 12–18, and 24 months after
SIg, CD11c, CD103) to detect MRD after one course of standard 2-CdA therapy. The rate of
therapy with 2-CdA. The definition for positive MRD negativity (defined as 51% staining with
MRD with IHC was 1–10% CD20/DBA44þscat- DBA.44) improved from 57% at the 2-month
tered or clustered cells with tricoleukocyte morphol- assessment to 77% at the 6-month assessment,
ogy, and with FC was any expression of CD11c/ without significant changes thereafter, suggesting
CD25/CD103 in the BM or40.3% of the B-cells in that it may take up to 6 months for the full effects
PB. The MRD positivity rate for IHC was 46% of the nucleoside analog therapy to manifest. There
compared with 64% for FC, suggesting that the latter was a correlation between DBA.44 immunostain-
was the more sensitive technique. MRD could not be ing45% on the 6-month marrow assessment and an
correlated with relapse owing to the small cohort increased incidence of relapse.
studied. Wheaton et al. [10] assessed MRD via IHC
As discussed previously, PCR techniques offer staining (anti-CD20, DBA.44, anti-CD45-RO) of
another potential modality for the detection of MRD. BMs after therapy with 2-CdA. Anti-CD45-RO was
Sausville et al. [5] performed a comparative analysis used to assay the T-cell population relative to cells
of PB multi-parameter FC (CD19, CD22, CD103, that stained positive for CD20 or DBA.44, given
FMC7, CD23, CD19, CD20, CD11c, CD25, prior observations that T-cells generally outnumber
CD45, CD4, CD8, CD3, CD5, CD7, CD2) and B-cells in nonneoplastic states. Hairy cell morphol-
cpPCR assays for the detection of MRD in previously ogy had to be present in at least 50% of the cells that
treated HCL. FC was more sensitive for detection of stained positive for CD20 or DBA.44. The incidence
disease because 31% of the cases positive by this of detectable MRD by IHC at 3 months after therapy
method were negative by cpPCR. In contrast, only was lower than the Ellison et al. study [2], likely
1% of cases positive by cpPCR were negative by FC. related to differences in the definition of MRD.
Arons et al. [6] compared the incidence of MRD Tallman et al. [11] then compared the outcomes by
positivity by FC, cpPCR, and spPCR after therapy status of MRD as assessed by IHC in the cohort
with the recombinant immunotoxin BL22 for pre- treated with 2-CdA (n¼39) described in the
viously treated HCL. The MRD positivity rates were Wheaton study [10] and a separate cohort treated
74%, 55%, and 98%, respectively. Quantitative levels with DCF (n¼27). BM sampling varied by therapy
of spPCR correlated with disease status. This report owing to protocol stipulations: 3 months, then yearly
and the prior study of Sausville et al. [5] suggest that after therapy with 2-CdA versus every 6 months after
FC is clearly superior to cpPCR for the detection of therapy with DCF. Relapse was defined as detection
MRD in HCL. Practically speaking, the use of of HCL via H & E microscopy of BM. Findings are
spPCR may be most useful once negativity for detailed in Table I. The prevalence of detectable
MRD by FC has been established. MRD by IHC was similar between the two nucleo-
A surrogate marker of disease burden includes side analogs, although the BMs were collected at
soluble serum interleukin-2 receptor (sIL-2R) levels different time points. The 4-year relapse-free survival
[7,8]. Decreasing sIL-2R levels correlate with im- rate was significantly lower if MRD was detected
provements in hematological parameters, reductions (55% versus 88%, p¼0.0025).
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