32.4.1. IgM HLC and WM diagnosisFigure 32.6) . Hevylite analysis may also be useful in cases where monoclonal proteins form multimers or co-migrate with other serum protein peaks (Section 17.4) .
Boyle et al.  assessed the diagnostic sensitivity of IgM HLC in 78 WM patients at presentation and showed that IgMκ/IgMλ HLC ratios were abnormal in all cases, including 12/78 patients with SPE bands that were non-quantifiable and 4/78 patients with total IgM concentrations within the normal range (Figure 32.7). Similar findings were reported by Koulieris et al.  who reported a diagnostic sensitivity for IgM Hevylite in WM of 97%.
32.4.2. Monitoring WM using IgM HLC
Preliminary evidence suggests that IgM HLC may be useful for monitoring response to treatment in WM . Manier et al.  compared the IgM response rate using SPE, IgM nephelometry and IgM HLC, for 10 WM patients who were treated as part of a Phase 3 trial. After 14 months, the proportion of patients achieving a partial response or better, vs. those who had stable disease, was similar across the three techniques. The median time to response and time to progression was also similar.
Koulieris et al.  monitored nine WM patients with IgM HLC. The involved HLC concentration and the IgMκ/IgMλ HLC ratio mostly followed disease fluctuations. During the study period patients only achieved a partial remission, and consistent with this, the IgM HLC ratio never normalised. Boyle et al.  compared HLC, SPE and total IgM results from 25 patients during follow-up. A proportion of patients could not be monitored using standard techniques (due to non-quantifiable bands on SPE [4/25] or oligosecretory disease [<10 g/L, 4/25]), but all 25 patients had abnormal HLC ratios at presentation and could be subsequently monitored using HLC assays. A comparison of the responses assigned using SPE or total IgM with the iHLC concentration, indicated an almost perfect agreement between the assays (weighted Kappa 0.84 and 0.86, respectively). Similar results were reported by Alvi et al.  Boyle et al.  noted however, that using standard assessments, 6/21 patients achieved a complete response, but in each case the HLC ratio indicated residual disease. In addition, 10/21 patients progressed and in each case the changes in the HLC ratio were consistent with the clinical findings.
An update of the consensus panel criteria for the assessment of clinical response in WM stated that further prospective evaluation of the use of HLC to assess response in WM is encouraged .
32.4.3. IgM HLC and WM prognosis studied the prognostic significance of IgM HLC in 31 WM patients at diagnosis. The median involved/uninvolved IgM HLC ratio was significantly higher in WM patients requiring treatment (n=24) compared with patients not requiring treatment (n=7) (185.7 vs. 13.45; p=0.023). Leleu et al.  reported similar data: the median involved/uninvolved HLC ratio was significantly higher in progressing symptomatic patients compared with asymptomatic patients (p=0.014). Patients with a higher involved/uninvolved HLC ratio (>median) had a significantly shorter time to treatment than those patients with a lower HLC ratio Figure 32.8A.
Koulieris et al.  also reported a correlation between the IgM HLC ratio and bone marrow infiltration (p=0.029) and time to first treatment (p=0.003); they proposed a risk stratification model that identified 3 prognostic groups with respect to survival. This model comprised 3 risk factors: involved/uninvolved IgM HLC ratio (>median); β2-microglobulin (>5.5 mg/L); and abnormal lactate dehydrogenase (LDH) (Figure 32.8B).
In a subsequent, larger study, Koulieris et al.  studied the prognostic significance of systemic hypogammaglobulinaemia and HLC pair suppression in 70 WM patients at diagnosis. HLC pair suppression (defined as IgMκ or IgMλ <0.1 g/L) was present in 26% (18/70) patients; whilst systemic hypogammaglobulinaemia (defined as IgG <7 g/L and/or IgA <0.7 g/L), was present in 49% (34/70) of patients. During follow-up (median 37 months), 48/70 patients were or became symptomatic and 16/70 died. Neither systemic hypogammaglobulinaemia nor HLC pair suppression at diagnosis correlated with time to first treatment (p=0.358) or overall survival (p=0.874). Conversely, Murillo-Florez et al.  found that relapsed/refractory WM patients had a mean uninvolved HLC concentration that was lower than the patients who did not relapse (0.29 vs. 0.52 g/L; p=0.04). Therefore, the prognostic utility of HLC pair measurement in WM has yet to be established.
Andrade-Campos et al.  evaluated the prognostic value of HLC pair suppression in 32 patients with asymptomatic WM. At diagnosis, an involved/uninvolved HLC ratio >62 identified a subset of patients with a shorter time to progression (108 vs. 133 months, p=0.033), and the authors concluded that HLC pair suppression was the major contributor to the prognostic value of the Hevylite assay.